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Drug Metabolism
METABOLISM OR BIOTRANSFORMATION
 The conversion from one chemical form of a substance to another.

 The term metabolism is commonly used probably because products of drug
  transformation are called metabolites.

 Metabolism is an essential pharmacokinetic process, which renders lipid soluble and
  non-polar compounds to water soluble and polar compounds so that they are
  excreted by various processes.
 This is because only water-soluble substances undergo excretion, whereas lipid
  soluble substances are passively reabsorbed from renal or extra renal excretory sites
  into the blood by virtue of their lipophilicity.

 Metabolism is a necessary biological process that limits the life of a substance in the
  body.

 Biotransformation: It is a specific term used for chemical transformation of
    xenobiotics in the body/living organism.
• a series of enzyme-catalyzed processes—that alters the physiochemical properties of
foreign chemicals (drug/xenobiotics) from those that favor absorption across biological
membranes (lipophilicity) to those favoring elimination in urine or bile (hydrophilicity )
Metabolism : It is a general term used for chemical
 transformation of xenobiotics and endogenous
 nutrients (e.g., proteins, carbohydrates and fats) within
 or outside the body.

Xenobiotics : These are all chemical substances that
 are not nutrient for body (foreign to body) and which
 enter the body through ingestion, inhalation or dermal
 exposure.

They include :
  drugs, industrial chemicals, pesticides, pollutants,
 plant and animal toxins, etc.
Functions of Biotransformation

It causes conversion of an
 active drug to inactive or
 less active metabolite(s)
 called as pharmacological
 inactivation.

It causes conversion of an
 active to more active
 metabolite(s) called as
 bioactivation             or
 toxicological activation.

• It causes conversion of an
  inactive to more active
  toxic metabolite(s) called
  as lethal synthesis
Functions of Biotransformation….contd

• It causes conversion of an
  inactive drug (pro-drug) to
  active metabolite(s) called
  as         pharmacological
  activation
• It causes conversion of an
  active drug to equally active
  metabolite(s) (no change in
  pharmacological activity)
• It causes conversion of an
  active drug to active
  metabolite(s)        having
  entirely           different
  pharmacological     activity
  (change in pharmacological
  activity)
Site/Organs of drug metabolism
The major site of drug metabolism is the liver
  (microsomal enzyme systems of hepatocytes)
Secondary organs of biotransformation
• kidney (proximal tubule)
• lungs (type II cells)
• testes (Sertoli cells)
• skin (epithelial cells); plasma. nervous tissue
  (brain); intestines
Sites of Biotransformation…contd
Liver
 The primary site for metabolism of almost all drugs because it is relatively
   rich in a large variety of metabolising enzymes.

 Metabolism by organs other than liver (called as extra-hepatic metabolism)
  is of lesser importance because lower level of metabolising enzymes is
  present in such tissues.

 Within a given cell, most drug metabolising activity is found in the smooth
  endoplasmic reticulum and the cytosol.
 Drug metabolism can also occur in mitochondria, nuclear envelope and
  plasma membrane.

 A few drugs are also metabolised by non-enzymatic means called as non-
  enzymatic metabolism.

 For example, atracurium, a neuromuscular blocking drug, is inactivated in
  plasma by spontaneous non-enzymatic degradation (Hoffman elimination)
  in addition to that by pseudocholinesterase enzyme.
Subcellular          Locations          of        Metabolizing            Enzymes
•   ENDOPLASMIC RETICULUM (microsomes): the primary location for the
    metabolizingenzymes.
•   (a) Phase I: cytochrome P450, flavin-containing monooxygenase, aldehydeoxidase,
    carboxylesterase, epoxide hydrolase, prostaglandin synthase, esterase.
•   (b) Phase II uridine diphosphate-glucuronosyltransferase, glutathione S-
    transferase, amino acid conjugating enzymes.
•   CYTOSOL (the soluble fraction of the cytoplasm): many water-soluble enzymes.
•    (a) Phase I: alcohol dehydrogenase, aldehyde reductase, aldehyde dehydrogenase,
    epoxide hydrolase, esterase.
•   (b) Phase 11: sulfotransferase, glutathione S-transferase, N-acetyl transferase,
    catechol 0-methyl transferase, amino acid conjugating enzymes.

•   MITOCHONDRIA.
•   (a) Phase I: monoamine oxidase, aldehyde dehydrogenase, cytochrome P450.
•   (b) Phase II: N-acetyl transferase, amino acid conjugating enzymes.
•   LYSOSOMES. Phase I: peptidase.
•   NUCLEUS.
•   Phase II: uridine diphosphate-glucuronosyltransferase (nuclear membrane of
    enterocytes).
Drug Metabolising Enzymes

A number of enzymes in animals are capable of metabolising
 drugs. These enzymes are located mainly in the liver, but may
 also be present in other organs like lungs, kidneys, intestine,
 brain, plasma, etc.

Majority of drugs are acted upon by relatively non-specific
 enzymes, which are directed to types of molecules rather than
 to specific drugs.

The drug metabolising enzymes can be broadly divided into two
 groups: microsomal and non-microsomal enzymes.
Microsomal enzymes: The endoplasmic reticulum (especially
 smooth endoplasmic reticulum) of liver and other tissues
 contain a large variety of enzymes, together called microsomal
 enzymes

(microsomes are minute spherical vesicles derived from
 endoplasmic reticulum after disruption of cells by
 centrifugation, enzymes present in microsomes are called
 microsomal enzymes).

They catalyse glucuronide conjugation, most oxidative
 reactions, and some reductive and hydrolytic reactions.

The monooxygenases, glucuronyl         transferase,   etc   are
 important microsomal enzymes.
Non-microsomal       enzymes:     Enzymes    occurring     in
 organelles/sites   other    than    endoplasmic    reticulum
 (microsomes) are called non-microsomal enzymes.

These are usually present in the cytoplasm, mitochondria, etc.
 and occur mainly in the liver, Gl tract, plasma and other tissues.

They are usually non-specific enzymes that catalyse few
 oxidative reactions, a number of reductive and hydrolytic
 reactions, and all conjugative reactions other than
 glucuronidation.

None of the non-microsomal enzymes involved in drug
 biotransformation is known to be inducible.
Drug metabolism
Drug Metabolism


Extrahepatic microsomal enzymes
    (oxidation, conjugation)




 Hepatic microsomal enzymes
    (oxidation, conjugation)




 Hepatic non-microsomal enzymes
 (acetylation, sulfation,GSH,
 alcohol/aldehyde dehydrogenase,
 hydrolysis, ox/red)
Factors Affecting Drug Metabolism

1. Species differences : eg in phenylbutazone, procaine and
   barbiturates.
2. Genetic differences – variation exist with species
3. Age of animal –feeble in fetus,aged, newborn.
4.sex: under the influence of sex hormones.
5. Nutrition: starvation and malnutrition
6. Patholigical conditions: Liver/Kidney dysfunction
TYPES OF BIOTRANSFORMATION
 Phase 1 reaction. (Non synthetic phase).        Phase II reaction. (Synthetic phase)
• a change in drug molecule. generally        • Last step in detoxification reactions
   results in the introduction of a               and almost always results in loss of
   functional group into molecules or the         biological activity of a compound.
   exposure of new functional groups of       • May be preceded by one or more of
   molecules                                      phase one reaction
 : Phase I (non-synthetic or non-            • Involves conjugation of functional
   conjugative phase) includes reactions          groups of molecules with hydrophilic
   which catalyse oxidation, reduction and        endogenous substrates- formation
   hydrolysis of drugs.                           of conjugates - is formed with (an
                                                  endogenous substance such as
                                                  carbohydrates and amino acids. )with
 In phase I reactions, small polar
                                                  drug or its metabolites formed in
  functional groups like-OH, -NH2. -SH, -
                                                  phase 1 reaction.
  COOH, etc. are either added or
  unmasked (if already present) on the         Involve attachment of small polar
  lipid soluble drugs so that the resulting     endogenous molecules like glucuronic
  products may undergo phase II                 acid, sulphate, methyl, amino acids,
  reactions.                                    etc., to either unchanged drugs or
                                                phase I products.
• result in activation, change or
  inactivation of drug.                        Products called as 'conjugates' are
                                                water-soluble metabolites, which are
                                                readily excreted from the body.
•   Phase I metabolism is sometimes called a •            Phase II metabolism includes what are known
    “functionalization reaction,”
                                                          as conjugation reactions.
•   Results in the introduction of new
    hydrophilic functional groups to compounds. •         Generally, the conjugation reaction with
•   Function: introduction (or unveiling) of              endogenous substrates occurs on the
    functional group(s) such as –OH, –NH2, –SH,           metabolite( s) of the parent compound after
    –COOH into the compounds.                             phase I metabolism; however, in some cases,
•   Reaction types: oxidation, reduction, and             the parent compound itself can be subject to
    hydrolysis                                            phase II metabolism.
                                                      •   Function: conjugation (or derivatization) of
•   Enzymes:                                              functional groups of a compound or its
•   Oxygenases and oxidases: Cytochrome P450 (P450        metabolite(s) with endogenous substrates.
    or CYP), flavincontaining
                                                      •   Reaction types: glucuronidation, sulfation,
•   monooxygenase (FMO), peroxidase, monoamine
    oxidase(MAO), alcohol dehydrogenase, aldehyde         glutathione-conjugation,            Nacetylation,
    dehydrogenase, and xanthine 0xidase. Reductase:       methylation and conjugation with amino acids
    Aldo-keto reductase and quinone reductase.            (e.g., glycine, taurine, glutamic acid).
•   Hydrolytic enzymes: esterase, amidase, aldehyde
    oxidase, and alkylhydrazine
                                                      •   Enzymes: Uridine diphosphate-Glucuronosyltransferase
                                                          (UDPGT): sulfotransferase (ST), N-acetyltransferase,
•   oxidase.
                                                          glutathione S-transferase (GST),methyl transferase, and
•   Enzymes that scavenge reduced oxygen:                 amino acid conjugating enzymes.
    Superoxide dismutases, catalase,
                                                      •    Glucuronidation       by        uridine        diphosphate-
•   glutathione peroxidase, epoxide hydrolase, y-         glucuronosyltransferase; Sulfation by sulfotransferase
    glutamyl transferase,
                                                      •   3. Acetylation by N-acetyltransferase;           Glutathione
•   dipeptidase, and cysteine conjugate β-lyase           conjugation by glutathione S-transferase;. Methylation by
                                                          methyl transferase; Amino acid conjugation
PHASE I BIOTRANSFORMATION



                                Oxidation

• Oxidation by cytochrome P450 isozymes (microsomal                mixed-
  functionoxidases).
• Oxidation by enzymes other than cytochrome P450s—most of these
• (a) oxidation of alcohol by alcohol dehydrogenase,
• (b) oxidation of aldehyde by aldehyde dehydrogenase,
• (c) N-dealkylation by monoamineoxidase.
Phase I Reactions
Oxidation :
• Oxidative reactions are most important metabolic reactions, as
energy in animals is derived by oxidative combustion of organic
molecules containing carbon and hydrogen atoms.

• The oxidative reactions are important for drugs because they
increase hydrophilicity of drugs by introducing polar functional
groups such as -OH.

• Oxidation of drugs is non-specifically catalysed by a number of
enzymes located primarily in the microsomes. Some of the
oxidation reactions are also catalysed by non-microsomal enzymes
(e.g., aldehyde dehydrogenase, xanthine oxidase and monoamine
oxidase).
The most important group of oxidative enzymes are microsomal
monooxygcnases or mixed function oxidases (MFO).

These enzymes are located mainly in the hepatic endoplasmic
reticulum and require both molecular oxygen (02) and reducing
NADPH to effect the chemical reaction.

Mixed function oxidase name was proposed in order to
characterise the mixed function of the oxygen molecule, which is
essentially required by a number of enzymes located in the
microsomes.
The term monooxygenses for the enzymes was proposed as they
incorporate only one atom of molecular oxygen into the organic substrate
with concomitant reduction of the second oxygen atom to water.

The overall stoichiometry of the reaction involving the substrate RH which
yields the product ROH, is given by the following reaction:
                           MFO
RH+02+NADPH+H+ ----------------► R0H+H20+NADP+
The most important component of mixed function oxidases is the
cytochrome P-450 because it binds to the substrate and activates oxygen.

The wide distribution of cytochrome P-450 containing MFOs in varying
organs makes it the most important group of enzymes involved in the
biotransformation of drugs.
Drug metabolism
Drug metabolism
 PHASE I ENZYMES            PHASE II ENZYMES
  Cytochrome P450            • Uridine          Diphosphate-
  Monooxygenase                Glucuronosyltransferase
  (Cytochrome P450, P450,      (UDPGT)
  or CYP)                    • Sulfotransferase (ST)
• Flavin-Containing          • N-Acetyltransferase (NAT)
  Monooxygenase (FMO)
                             • Glutathione      S-Transferase
• Esterase                     (GST)
• Alcohol Dehydrogenase      • Methyl Transferase
  (ADH)
                             • Amino Acid Conjugation
• Aldehyde
  Dehydrogenase (ALDH)
• Monoamine        Oxidase
  (MAO)
The cytochrome P-450 ENZYMES
• Superfamily of haem-thiolate proteins that are widely distributed
across all living creatures.
• The name given to this group of proteins because their reduced
form binds with carbon monoxide to form a complex, which has
maximum absorbance at 450 nm.
• Depending upon the extent of amino acid sequence homology, the
cytochrome P-450 (CYP) enzymes superfamily contains a number of
isoenzymes, the relative amount of which differs among species and
among individuals of the same species.
• These isoenzymes are grouped into various families designated by
Arabic numbers 1, 2, 3 (sequence that are greater than 40% identical
belong to the same family), each having several subfamilies
designated by Capital letter A, B, C, while individual isoenzymes are
again allotted Arabic numbers 1.2,3 (e.g., CYP1A1, CYP1A2, etc.).
Drug metabolism
ROLE OF CYP ENZYMES IN HEPATIC DRUG METABOLISM
In human beings, of the 1000 currently known cytochrome P-450s, about 50 are functionally
active. These are categorised into 17 families, out of which the isoenzymes CYP3A4 and CYP2D6
carry out biotransformation of largest number of drugs.




RELATIVE HEPATIC CONTENT                                % DRUGS METABOLIZED
    OF CYP ENZYMES                                         BY CYP ENZYMES
                CYP2E1
    CYP2D6        7%
      2%


                                                              CYP 2C19
                                                                11%
                                                   CYP 2C9
      CYP 2C                                        14%
                                                                          CYP2D6
       17%
                                                                           23%
                            OTHER
                             36%
                                                 CYP 1A2
     CYP 1A2                                      14%
      12%

               CYP 3A4-5                                                                CYP2E1
                                                             CYP 3A4-5
                 26%                                                                      5%
                                                               33%
Drug metabolism
Participation of the CYP Enzymes in Metabolism of Some
Clinically Important Drugs

CYP Enzyme Examples of substrates
1A1          Caffeine, Testosterone, R-Warfarin
1A2          Acetaminophen, Caffeine, Phenacetin, R-Warfarin
2A6          17 -Estradiol, Testosterone
2B6          Cyclophosphamide, Erythromycin, Testosterone
2C-family    Acetaminophen, Tolbutamide (2C9); Hexobarbital, S-
             Warfarin (2C9,19); Phenytoin, Testosterone, R- Warfarin,
             Zidovudine (2C8,9,19);
2E1          Acetaminophen, Caffeine, Chlorzoxazone, Halothane
2D6          Acetaminophen, Codeine, Debrisoquine
3A4          Acetaminophen, Caffeine, Carbamazepine, Codeine,
             Cortisol, Erythromycin, Cyclophosphamide, S- and R-
             Warfarin, Phenytoin, Testosterone, Halothane, Zidovudine
2. Reduction :
Reduction
Enzymes responsible for reduction of xenobiotics require NADPH as a cofactor.
Substrates for reductive reactions include azo- or nitrocompounds, epoxides,
heterocyclic compounds, and halogenated hydrocarbons:
(a) Azo or nitroreduction by cytochrome P450;
(b) Carbonyl (aldehyde or ketone) reduction by aldehyde reductase, aldose
    reductase, carbonyl reductase, quinone reductase
(c) other reductions including disulfide reduction, sulfoxide reduction, and
    reductive dehalogenation.
The acceptance of one or more electron(s) or their equivalent from another
substrate.

Reductive reactions, which usually involve addition of hydrogen to the drug
molecule, occur less frequently than the oxidative reactions.

Biotransformation by reduction is also capable of generating polar functional
groups such as hydroxy and amino groups, which can undergo further
biotrans-formation.
 Many reductive reactions are exact opposite of the oxidative reactions
   (reversible reactions) catalysed cither by the same enzyme (true reversible
   reaction) or by different enzymes (apparent reversible reactions).

 Such reversible reactions usually lead to conversion of inactive metabolite
  into active drug, thereby delaying drug removal from the body.
Drug metabolism
3. Hydrolysis :
Esters, amides, hydrazides, and carbamates can be hydrolyzed by
various
enzymes.
 The hydrolytic reactions, contrary to oxidative or reductive
  reactions, do not involve change in the state of oxidation of the
  substrate, but involve the cleavage of drug molecule by taking up
  a molecule of water.

The hydrolytic enzymes that metabolise drugs are the ones that
 act on endogenous substances, and their activity is not confined
 to liver as they are found in many other organs like kidneys,
 intestine, plasma, etc.

A number of drugs with ester, ether, amide and hydrazide
 linkages undergo hydrolysis. Important examples are
 cholinesters, procaine, procainamide, and pethidine.
Drug metabolism
PHASE II REACTIONS

 Phase II or conjugation (Latin, conjugatus = yoked together)
  reactions involve combination of the drug or its phase I
  metabolite with an endogenous substance to form a highly polar
  product, which can be efficiently excreted from the body.

 In the biotransformation of drugs, such products or metabolites
  have two parts:
 Exocon, the portion derived from exogenous compound or
  xenobiotic,
 Endocon, the portion derived from endogenous substance.

 Conjugation reactions have high energy requirement and they
  often utilise suitable enzymes for the reactions.
The endogenous substances (endocons) for conjugation
 reactions are derived mainly from carbohydrates or amino acids
 and usually possess large molecular size.

 They are strongly polar or ionic in nature in order to render the
 substrate water-soluble. The molecular weight of the conjugate
 (metabolite) is important for determining its route of excretion.

High molecular weight conjugates are excreted predominantly in
 bile (e.g., glutathione exclusively, glucuronide mainly),
while low molecular weight conjugates are excreted mainly in the
 urine.

As the availability of endogenous conjugating substance is limited,
 saturation of this process is possible and the unconjugated
 drug/metabolite may precipitate toxicity.
1. Conjugation with glucuronic a./ Glucuronidation

 Conjugation with glucuronic acid (glucuronide conjugation or
  glucuroni-dation) is the most common and most important
  phase II reaction in vertebrates, except cats and fish.

 The biochemical donor (cofactor) of glucuronic acid is uridine
  diphosphate«-D-glucuronicacid (UDPGA) and the reaction is
  carried out by enzyme uridine diphosphate-glucuronyl
  transferase   (UDP-giucuronyl     transferase;     glucuronyl
  transferase).

 Glucuronyl transferase is present in microsomes of most
  tissues but liver is the most active site of glucuronide
  synthesis.
 Glucuronidation can take place in most body tissues because
  the glucuronic acid donor UDPGA is present in abundant
  quantity in body, unlike donors involved in other phase II
  reactions.

 In cats, there is reduced glucuronyl transferase activity, while
  in fish there is deficiency of endogenous glucuronic acid donor.

 The limited capacity of this metabolic pathway in cats may
  increase the duration of action, pharmacological response and
  potential of toxicity of several lipid-soluble drugs (e.g., aspirin)
  in this species.
 A large number of drugs undergo glucuronidation including
  morphine, paracetamol and desipramine. Certain endogenous
  substances such as steroids, bilirubin, catechols and thyroxine
  also form glucuronides.

 Deconjugaiion process: Occasionally some glucuronide
  conjugates that are excreted in bile undergo deconjugation
  process in the intestine mainly mediated by β glucuronidase
  enzyme.

 This releases free and active drug in the intestine, which may be
  reabsorbed and undergo entero-hepatic cycling.

 Deconjugation is an important process because it often prolongs
  the pharmacological effects of drugs and/or produces toxic
  effects.
2. Conjugation with sulphate/ Sulphation:

 Conjugation     with   sulphate     (sulphate    conjugation,
  sulphoconjugation orsulphation) is similar to glucuronidation
  but is catalysed by non-microsomal enzymes and occurs less
  commonly.

 The endogenous donor of the sulphate group is 3'-
  phosphoadenosine-5'-phosphosulphate (PAPS), and enzyme
  catalysing the reaction is sulphotransferase
The conjugates of sulphate are referred to as sulphate ester
conjugates or ethereal sulphates. Unlike glucuronide
conjugation, sulphoconjugation in mammals is less important
because the PAPS donor that transfers sulphate to the substrate
is easily depleted.

 Capacity for sulphate conjugation is limited in pigs. However
in cats, where glucuronidation is deficient, sulphate conjugation
is important. Functional groups capable of forming sulphate
conjugates include phenols, alcohols, arylamines, N-
hydroxylamines and N-hydroxyamides.

 Drugs    undergoing       sulphate    conjugation     include
chloramphenicol, phenols, and adrenal and sex steroids.
3. Conjugation with methyl group/ Methylation :

 Conjugation with methyl group (methyl conjugation or
  methylation) involves transfer of a methyl group (-CH3) from the
  cofactor S-adenosyl methionine (SAM) to the acceptor substrate
  by various methyl transferase enzymes.

 Methylation reaction is of lesser importance for drugs, but is
  more important for biosynthesis (e.g., adrenaline, melatonin)
  and | Inactivation (e.g., histamine) of endogenous amines.

 Occasionally, the metabolites formed are not polar or water-
  soluble and may possess equal or greater activity than the
  parent compound (e.g., adrenaline synthesised from
  noradrenaline).
4. Conjugation with glutathione and mercapturic acid formation.

 Conjugation with glutathione (glutathione conjugation) and mercapturic acid formation
is a minor but important metabolic pathway in animals.

 Glutathione (GSH, G=glutathione and SH = active-SH group) is a tripeptide having
glutamic acid, cysteine and glycine.

 It has a strong nucleophilic character due to the presence of a -SH (thiol) group in its
structure. Thus, it conjugates with electrophilic substrates, a number of which are
potentially toxic compounds, and protects the tissues from their adverse effects.

 The interaction between the substrate and the GSH is catalysed by enzyme glutathione-
  S-transferase, which is located in the soluble fraction of liver homogenates.

 The glutathione conjugate either due to its high molecular weight is excreted as such in
  the bile or is further metabolised to form mercapturic acid conjugate that is excreted in
  the urine.
5. Conjugation with acetyl group/ Acetylation :

 Conjugation with acetyl group (acetylation) is an important
  metabolic pathway for drugs containing the amino groups.

 The cofactor for these reactions is acetyl coenzyme A and the
  enzymes are non-microsomal N-acetyl transferases, located in
  the soluble fraction of cells of various tissues.

 Acetylation is not a true detoxification process because
  occasionally it results in decrease in water solubility of an amine
  and. thus, increase in its toxicity (e.g., sulphonamides).
 Acetylation is the primary route of biotransformation of
  sulphonamide compounds. Dogs and foxes do not acetylate
  the aromatic amino groups due to deficiency of arylamine
  acetyltransferase enzyme.

 Conjugation with amino acids : Conjugation with amino acids
  occurs to a limited extent in animals because of limited
  availability of amino acids. The most important reaction
  involves conjugation with glycine.

 Conjugation with other amino acids like glutamine in man and
  ornithine in birds is also seen.

 Examples of drugs forming glycine or glutamine conjugates are
  salicylic acid, nicotinic acid and cholic acid.
Conjugation with thiosulphate : Conjugation with thiosulphate is
an important reaction in the detoxification of cyanide. Conjugation
of cyanide ion involves transfer of sulphur atom from the
thiosulphate to the cyanide ion in presence of enzyme rhodancse
to form inactive thiocyanate.

Thiocyanate formed is much less toxic than the cyanide (true
detoxification) and it is excreted in urine.
Drug metabolism
Drug metabolism
INDUCTION OF METABOLISM
 Administration of certain xenobiotics sometimes results in a
selective increase in the concentration of metabolizing enzymes in
both phase I and II metabolism, and thereby in their activities
 Enzyme induction becomes important especially when
polypharmacy involves drugs with narrow therapeutic windows, since
the induced drug metabolism could result in a significant decrease in
its exposure and therapeutic effects.
 In addition, enzyme induction may cause toxicity, associated with
increased production of toxic metabolites.
 Mechanisms of Induction
 Stimulation of transcription of genes and/or translation of proteins,
and/or stabilization of mRNA and/or enzymes by inducers, resulting in
elevated enzyme levels.
 Stimulation of preexisting enzymes resulting in apparent
enzyme induction without an increase in enzyme synthesis (this
is more common in vitro than in vivo).
 In many cases, the details of the induction mechanisms are
unknown.
 TWO receptors have been identified for CYPlA1/2 and
CYP4A1/2induction:
(a) Ah (aromatic hydrocarbon) receptor in cytosol, which
regulates enzyme (CYP1 A1 and 1A2) induction by polycyclic
aromatic hydrocarbon (PAH)-type inducers;
(b) Peroxisome proliferator activated receptor (PPAR), where
    hypolipidemic agents cause peroxisome proliferation in rats
(CYP4A1 and 4A2);-humans have low PPAR and show no
effects from hypolipidemic agents.
Characteristics of Induction
 Induction is a function of intact cells and cannot be achieved by treating
isolated cell fractions such as microsomes with inducers.
 Evaluation of enzyme induction is usually conducted in ex vivo experiments,
ie., treating animals in vivo with potential inducers and measuring enzyme
activities in vitro or in cell-based in vitro preparations such as hepatocytes, liver
slices, or cell lines.
 Recent studies have demonstrated that primary cultures of hepatocytes can
be used for studying the inducibility of metabolizing enzymes such as P450 under
certain incubation conditions
 Enzyme induction is usually inducer-concentration–dependent. The extent of
induction increases as the inducer concentration increases; however, above
certain values, induction starts to decline.
 In general, inducers increase the content of endoplasmic reticulum within
hepatocytes as well as liver weight.
 In some cases, an inducer induces enzymes responsible for its own
metabolism (so-called “autoinduction”).
Induction of Drug Metabolising Enzymes

 Several drugs and chemicals have ability to increase the drug
  metabolising activity of enzymes called as enzyme induction.

 These drugs known as enzyme inducers mainly interact with DNA and
  increase the synthesis of microsomal enzyme proteins, especially
  cytochrome P-450 and glucuronyl transferase.

 As a result, there is enhanced metabolism of endogenous substances
  (e.g., sex steroids) and drugs metabolised by microsomal enzymes.
  Some drugs (e.g., carbamazepine and rifampicin) may stimulate their
  own metabolism, the phenomenon being called as auto-induction or
  self induction.
Since different cytochrome P450 isoenzymes are involved in the
metabolism of different drugs, enzyme induction by one drug affects
metabolism of only those drugs, which are substrate for the induced
isoenzyme.

However, some drugs like Phenobarbitone may affect metabolism of a
large number of drugs because they induce isoenzymes like CYP3A4 and
CYP2D6 which act on many drugs.

Enzyme inducers are generally lipid-soluble compounds with relatively long
plasma half-lives.

Repeated administration of inducers for a few days (3 to 10 days) is often
required for enzyme induction, and on stoppage of drug administration,
the enzymes return to their original value over 1 to 3 weeks.

Non-microsomal enzymes are not known to be induced by any drug or
chemical.
Drug metabolism
Clinical importance of enzyme induction

 It reduces efficacy and potency of drugs metabolised by these
  enzymes.

 It reduces plasma half-life and duration of action of drugs.

 It enhances drug tolerance.

 It increases drug toxicity by enhancing concentration of
  metabolite, if metabolite is toxic.

 It increases chances of drug interactions.

 It alters physiological status of animal due to altered metabolism
  of endogenous compounds like sex steroids.
Inhibition of Drug Metabolising Enzymes

 Contrary to metabolising enzyme induction, several drugs or
chemicals have the ability to decrease the drug metabolising activity of
certain enzymes called as enzyme inhibition.

 Enzyme inhibition can be either non-specific of microsomal enzymes
or specific of some non-microsomal enzymes (e.g., monoamine oxidase,
cholinesterase and aldehyde dehydrogenase).

 The inhibition of hepatic microsomal enzymes mainly occurs due to
administration of hepatotoxic agents,
which cause either rise in the rate of enzyme degradation (e.g., carbon
tetrachloride and carbon disulphide) or fall in the rate of enzyme synthesis
(e.g., Puromycin and Dactinomycin).
 Nutritional deficiency, hormonal imbalance or hepatic
dysfunction, etc.also inhibit microsomal enzymes indirectly.

 Inhibition of non-microsomal enzymes with specific function
usually results when Structurally similar compounds compete for
the active site on the enzymes.

 Such an inhibition is usually rapid (a single dose of inhibitor
may be sufficient) and clinically more important than the non-
specific microsomal enzyme inhibition.

 Enzyme inhibition generally results in depressed metabolism
of drugs.
As a result, the plasma hall-life, duration of action, and efficacy
as well toxicity of the object drug (whose metabolism has been
inhibited) are significantly enhanced.
 In case the drug undergoes hepatic first-pass effect, the
bioavailability and toxicity Of the drug will be markedly increased
in presence of enzyme inhibition. Enzyme inhibition may also
produce undesirable drug interactions.

 In therapeutics, some specific enzyme inhibitors like
monoamine oxidase inhibitors, cholinesterase inhibitors and
angiotensin converting enzyme (ACE) inhibitors are purposely
used for producing desirable pharmacological actions
Inducing Agents
  In general, enzyme inducers are lipophilic at physiological pH and
exhibit relatively long t 1/2 with high accumulation in the liver.

Different classes of enzyme inducers.
1. Barbiturates: Phenobarbitone, Phenobarbital.
2. Polycyclic aromatic hydrocarbons (PAH): 3-methylcholanthrene (3-MC),
2,3,7,8,-tetrachlorodibenzo-p-dioxin (TCDD), β-naphthoflavone β ( -NF).
3. Steroids: Pregnenalone 16-α -carbonitrile (PCN), Dexamethasone.
4. Simple hydrocarbons with aliphatic chains: Ethanol (chronic), Acetone,
5. Hypolipidemic agents: Clofibrate, lauric acids.
6. Macrolide antibiotics: Triacetyloleandomycin (TAO).
7. A wide variety of structurally unrelated compounds: e.g., Antipyrine,
Carisoniazid. Bamazepine, Phenytoin, and Rifampicin
Drug metabolism
Drug metabolism
Drug metabolism
Drug metabolism
EXTRAHEPATIC METABOLISM
 Most tissues have some metabolic activity; however,
quantitatively the liver is by far the most important organ for drug
metabolism.

Important organs for extrahepatic metabolism include the
intestine (enterocytes and intestinal microflora), kidney, lung,
plasma, blood cells, placenta, skin, and brain.

 In general, the extent of metabolism in the major extrahepatic
drug-metabolizing organs such as the small intestine, kidney, and
lung is approximately 10–20% of the hepatic metabolism.

 Less than 5% of extrahepatic metabolism compared to hepatic
metabolism can be considered low with negligible
pharmacokinetic implications
First-Pass Effect/First-Pass Metabolism

 First-pass effect (first-pass metabolism or pre-systemic metabolism) may be defined
  as the loss of drug through biotransformation before it enters systemic circulation.

 This may occur during passage of drug for first time (therefore called first-pass
  effect/metabolism) through intestine or liver after oral administration.

 Intestinal first-pass effect: In this type, drugs are metabolised in the gastrointestinal
  tract by enzymes present in either gut mucosa or gut lumen before they are
  absorbed
 Recent studies have indicated that P450 isoforms such as CYP2C19 and 3A4 in
  enterocytes might play an important role in the presystemic intestinal metabolism of
  drugs and the large interindividual variability in systemic exposure after oral
  administration
 The cytochrome P450 content of the intestine is about 35% of the hepatic content
  in the rabbit, but accounts for only 4% of the hepatic content in the mouse.
  Cytochrome P450 levels and activities are highest in the duodenum near the
  pyrolus, and then decrease toward the colon
 A similar trend in regional activity levels along the intestine has been observed for
  glucuronide, sulfate, and glutathione conjugating enzymes.
 Microorganisms present in the GI tract also inactivate some drugs.
  Such drugs are not suitable by oral administration due to poor
  bioavailability (e.g., catecholamines).

 Hepatic first-pass effect: In this type, drugs are suitably absorbed
  across the GI tract and enter portal circulation, but they are rapidly
  and significantly metabolised during the first passage through the
  liver.

 (Normally, when a drug is absorbed across GI tract, it first enters the
  portal vein and passes through liver before it reaches the systemic
  circulation).

 Such drugs are also not/less suitable by oral administration due to
  their poor bioavailability. Examples of drugs undergoing significant
  hepatic first-pass effect include Propranolol, Lignocaine and
  Nitro-glycerine.
The rate and extent of first-pass intestinal metabolism of a drug
after oral administration are dependent on various physiological
factors
1. Site of absorption: If the absorption site in the intestine is different
from the metabolic site, first-pass intestinal metabolism of a drug
may not be significant.
2. Intracellular residence time of drug molecules in enterocytes: The
longer the drug molecules stay in the enterocytes prior to entering
the mesenteric vein, the more extensive the metabolism.
3. Diffusional barrier between splanchnic bed and enterocytes: The
lower the diffusibility of a drug from the enterocytes to the
mesenteric vein, the longer its residence time.
4. Mucosal blood flow: Blood in the splanchnic bed can act as a sink
to carry drug molecules away from the enterocytes, which reduces
intracellular residence time of drug in the enterocytes
Renal Metabolism
 In addition to physiological functions of homeostasis in water and
electrolytes and the excretion of endogenous and exogenous compounds
from the body, the kidneys are the site of significant biotransformation
activities for both phase I and phase II metabolism.
 The renal cortex, outer medulla, and inner medulla exhibit different
profiles of drug metabolism, which appears to be due to heterogeneous
distribution of metabolizing enzymes along the nephron.
 Most metabolizing enzymes are localized mainly in the proximal tubules,
although various enzymes are distributed in all segments of the nephron
 The pattern of renal blood flow, pH of the urine, and the urinary
concentrating mechanism can provide an environment that facilitates the
precipitation of certain compounds, including metabolites formed within the
kidneys.
 The high concentration or crystallization of xenobiotics and/or their
metabolites can potentially cause significant renal impairment in specific
regions of the kidneys.
Metabolism in Blood
 Blood contains various proteins and enzymes.
 As metabolizing enzymes, esterases, including cholinesterase,
arylesterase, and carboxylesterase, have the most significant effects
on hydrolysis of compounds with ester, carbamate, or phosphate
bonds in blood .
 Esterase activity can be found mainly in plasma, with less activity in
red blood cells.
 Plasma albumin itself may also act as an esterase under certain
conditions.
 For instance, albumin contributes about 20% of the total hydrolysis
of aspirin to salicylic acid in human plasma.
 The esterase activity in blood seems to be more extensive in small
animals such as rats than in large animals and humans. Limited, yet
significant monoamine oxidase activities can be also found in blood.
THANK YOU

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Drug metabolism

  • 2. METABOLISM OR BIOTRANSFORMATION  The conversion from one chemical form of a substance to another.  The term metabolism is commonly used probably because products of drug transformation are called metabolites.  Metabolism is an essential pharmacokinetic process, which renders lipid soluble and non-polar compounds to water soluble and polar compounds so that they are excreted by various processes.  This is because only water-soluble substances undergo excretion, whereas lipid soluble substances are passively reabsorbed from renal or extra renal excretory sites into the blood by virtue of their lipophilicity.  Metabolism is a necessary biological process that limits the life of a substance in the body.  Biotransformation: It is a specific term used for chemical transformation of xenobiotics in the body/living organism. • a series of enzyme-catalyzed processes—that alters the physiochemical properties of foreign chemicals (drug/xenobiotics) from those that favor absorption across biological membranes (lipophilicity) to those favoring elimination in urine or bile (hydrophilicity )
  • 3. Metabolism : It is a general term used for chemical transformation of xenobiotics and endogenous nutrients (e.g., proteins, carbohydrates and fats) within or outside the body. Xenobiotics : These are all chemical substances that are not nutrient for body (foreign to body) and which enter the body through ingestion, inhalation or dermal exposure. They include : drugs, industrial chemicals, pesticides, pollutants, plant and animal toxins, etc.
  • 4. Functions of Biotransformation It causes conversion of an active drug to inactive or less active metabolite(s) called as pharmacological inactivation. It causes conversion of an active to more active metabolite(s) called as bioactivation or toxicological activation. • It causes conversion of an inactive to more active toxic metabolite(s) called as lethal synthesis
  • 5. Functions of Biotransformation….contd • It causes conversion of an inactive drug (pro-drug) to active metabolite(s) called as pharmacological activation • It causes conversion of an active drug to equally active metabolite(s) (no change in pharmacological activity) • It causes conversion of an active drug to active metabolite(s) having entirely different pharmacological activity (change in pharmacological activity)
  • 6. Site/Organs of drug metabolism The major site of drug metabolism is the liver (microsomal enzyme systems of hepatocytes) Secondary organs of biotransformation • kidney (proximal tubule) • lungs (type II cells) • testes (Sertoli cells) • skin (epithelial cells); plasma. nervous tissue (brain); intestines
  • 7. Sites of Biotransformation…contd Liver  The primary site for metabolism of almost all drugs because it is relatively rich in a large variety of metabolising enzymes.  Metabolism by organs other than liver (called as extra-hepatic metabolism) is of lesser importance because lower level of metabolising enzymes is present in such tissues.  Within a given cell, most drug metabolising activity is found in the smooth endoplasmic reticulum and the cytosol.  Drug metabolism can also occur in mitochondria, nuclear envelope and plasma membrane.  A few drugs are also metabolised by non-enzymatic means called as non- enzymatic metabolism.  For example, atracurium, a neuromuscular blocking drug, is inactivated in plasma by spontaneous non-enzymatic degradation (Hoffman elimination) in addition to that by pseudocholinesterase enzyme.
  • 8. Subcellular Locations of Metabolizing Enzymes • ENDOPLASMIC RETICULUM (microsomes): the primary location for the metabolizingenzymes. • (a) Phase I: cytochrome P450, flavin-containing monooxygenase, aldehydeoxidase, carboxylesterase, epoxide hydrolase, prostaglandin synthase, esterase. • (b) Phase II uridine diphosphate-glucuronosyltransferase, glutathione S- transferase, amino acid conjugating enzymes. • CYTOSOL (the soluble fraction of the cytoplasm): many water-soluble enzymes. • (a) Phase I: alcohol dehydrogenase, aldehyde reductase, aldehyde dehydrogenase, epoxide hydrolase, esterase. • (b) Phase 11: sulfotransferase, glutathione S-transferase, N-acetyl transferase, catechol 0-methyl transferase, amino acid conjugating enzymes. • MITOCHONDRIA. • (a) Phase I: monoamine oxidase, aldehyde dehydrogenase, cytochrome P450. • (b) Phase II: N-acetyl transferase, amino acid conjugating enzymes. • LYSOSOMES. Phase I: peptidase. • NUCLEUS. • Phase II: uridine diphosphate-glucuronosyltransferase (nuclear membrane of enterocytes).
  • 9. Drug Metabolising Enzymes A number of enzymes in animals are capable of metabolising drugs. These enzymes are located mainly in the liver, but may also be present in other organs like lungs, kidneys, intestine, brain, plasma, etc. Majority of drugs are acted upon by relatively non-specific enzymes, which are directed to types of molecules rather than to specific drugs. The drug metabolising enzymes can be broadly divided into two groups: microsomal and non-microsomal enzymes.
  • 10. Microsomal enzymes: The endoplasmic reticulum (especially smooth endoplasmic reticulum) of liver and other tissues contain a large variety of enzymes, together called microsomal enzymes (microsomes are minute spherical vesicles derived from endoplasmic reticulum after disruption of cells by centrifugation, enzymes present in microsomes are called microsomal enzymes). They catalyse glucuronide conjugation, most oxidative reactions, and some reductive and hydrolytic reactions. The monooxygenases, glucuronyl transferase, etc are important microsomal enzymes.
  • 11. Non-microsomal enzymes: Enzymes occurring in organelles/sites other than endoplasmic reticulum (microsomes) are called non-microsomal enzymes. These are usually present in the cytoplasm, mitochondria, etc. and occur mainly in the liver, Gl tract, plasma and other tissues. They are usually non-specific enzymes that catalyse few oxidative reactions, a number of reductive and hydrolytic reactions, and all conjugative reactions other than glucuronidation. None of the non-microsomal enzymes involved in drug biotransformation is known to be inducible.
  • 13. Drug Metabolism Extrahepatic microsomal enzymes (oxidation, conjugation) Hepatic microsomal enzymes (oxidation, conjugation) Hepatic non-microsomal enzymes (acetylation, sulfation,GSH, alcohol/aldehyde dehydrogenase, hydrolysis, ox/red)
  • 14. Factors Affecting Drug Metabolism 1. Species differences : eg in phenylbutazone, procaine and barbiturates. 2. Genetic differences – variation exist with species 3. Age of animal –feeble in fetus,aged, newborn. 4.sex: under the influence of sex hormones. 5. Nutrition: starvation and malnutrition 6. Patholigical conditions: Liver/Kidney dysfunction
  • 15. TYPES OF BIOTRANSFORMATION Phase 1 reaction. (Non synthetic phase). Phase II reaction. (Synthetic phase) • a change in drug molecule. generally • Last step in detoxification reactions results in the introduction of a and almost always results in loss of functional group into molecules or the biological activity of a compound. exposure of new functional groups of • May be preceded by one or more of molecules phase one reaction  : Phase I (non-synthetic or non- • Involves conjugation of functional conjugative phase) includes reactions groups of molecules with hydrophilic which catalyse oxidation, reduction and endogenous substrates- formation hydrolysis of drugs. of conjugates - is formed with (an endogenous substance such as carbohydrates and amino acids. )with  In phase I reactions, small polar drug or its metabolites formed in functional groups like-OH, -NH2. -SH, - phase 1 reaction. COOH, etc. are either added or unmasked (if already present) on the  Involve attachment of small polar lipid soluble drugs so that the resulting endogenous molecules like glucuronic products may undergo phase II acid, sulphate, methyl, amino acids, reactions. etc., to either unchanged drugs or phase I products. • result in activation, change or inactivation of drug.  Products called as 'conjugates' are water-soluble metabolites, which are readily excreted from the body.
  • 16. Phase I metabolism is sometimes called a • Phase II metabolism includes what are known “functionalization reaction,” as conjugation reactions. • Results in the introduction of new hydrophilic functional groups to compounds. • Generally, the conjugation reaction with • Function: introduction (or unveiling) of endogenous substrates occurs on the functional group(s) such as –OH, –NH2, –SH, metabolite( s) of the parent compound after –COOH into the compounds. phase I metabolism; however, in some cases, • Reaction types: oxidation, reduction, and the parent compound itself can be subject to hydrolysis phase II metabolism. • Function: conjugation (or derivatization) of • Enzymes: functional groups of a compound or its • Oxygenases and oxidases: Cytochrome P450 (P450 metabolite(s) with endogenous substrates. or CYP), flavincontaining • Reaction types: glucuronidation, sulfation, • monooxygenase (FMO), peroxidase, monoamine oxidase(MAO), alcohol dehydrogenase, aldehyde glutathione-conjugation, Nacetylation, dehydrogenase, and xanthine 0xidase. Reductase: methylation and conjugation with amino acids Aldo-keto reductase and quinone reductase. (e.g., glycine, taurine, glutamic acid). • Hydrolytic enzymes: esterase, amidase, aldehyde oxidase, and alkylhydrazine • Enzymes: Uridine diphosphate-Glucuronosyltransferase (UDPGT): sulfotransferase (ST), N-acetyltransferase, • oxidase. glutathione S-transferase (GST),methyl transferase, and • Enzymes that scavenge reduced oxygen: amino acid conjugating enzymes. Superoxide dismutases, catalase, • Glucuronidation by uridine diphosphate- • glutathione peroxidase, epoxide hydrolase, y- glucuronosyltransferase; Sulfation by sulfotransferase glutamyl transferase, • 3. Acetylation by N-acetyltransferase; Glutathione • dipeptidase, and cysteine conjugate β-lyase conjugation by glutathione S-transferase;. Methylation by methyl transferase; Amino acid conjugation
  • 17. PHASE I BIOTRANSFORMATION Oxidation • Oxidation by cytochrome P450 isozymes (microsomal mixed- functionoxidases). • Oxidation by enzymes other than cytochrome P450s—most of these • (a) oxidation of alcohol by alcohol dehydrogenase, • (b) oxidation of aldehyde by aldehyde dehydrogenase, • (c) N-dealkylation by monoamineoxidase.
  • 18. Phase I Reactions Oxidation : • Oxidative reactions are most important metabolic reactions, as energy in animals is derived by oxidative combustion of organic molecules containing carbon and hydrogen atoms. • The oxidative reactions are important for drugs because they increase hydrophilicity of drugs by introducing polar functional groups such as -OH. • Oxidation of drugs is non-specifically catalysed by a number of enzymes located primarily in the microsomes. Some of the oxidation reactions are also catalysed by non-microsomal enzymes (e.g., aldehyde dehydrogenase, xanthine oxidase and monoamine oxidase).
  • 19. The most important group of oxidative enzymes are microsomal monooxygcnases or mixed function oxidases (MFO). These enzymes are located mainly in the hepatic endoplasmic reticulum and require both molecular oxygen (02) and reducing NADPH to effect the chemical reaction. Mixed function oxidase name was proposed in order to characterise the mixed function of the oxygen molecule, which is essentially required by a number of enzymes located in the microsomes.
  • 20. The term monooxygenses for the enzymes was proposed as they incorporate only one atom of molecular oxygen into the organic substrate with concomitant reduction of the second oxygen atom to water. The overall stoichiometry of the reaction involving the substrate RH which yields the product ROH, is given by the following reaction: MFO RH+02+NADPH+H+ ----------------► R0H+H20+NADP+ The most important component of mixed function oxidases is the cytochrome P-450 because it binds to the substrate and activates oxygen. The wide distribution of cytochrome P-450 containing MFOs in varying organs makes it the most important group of enzymes involved in the biotransformation of drugs.
  • 23.  PHASE I ENZYMES PHASE II ENZYMES Cytochrome P450 • Uridine Diphosphate- Monooxygenase Glucuronosyltransferase (Cytochrome P450, P450, (UDPGT) or CYP) • Sulfotransferase (ST) • Flavin-Containing • N-Acetyltransferase (NAT) Monooxygenase (FMO) • Glutathione S-Transferase • Esterase (GST) • Alcohol Dehydrogenase • Methyl Transferase (ADH) • Amino Acid Conjugation • Aldehyde Dehydrogenase (ALDH) • Monoamine Oxidase (MAO)
  • 24. The cytochrome P-450 ENZYMES • Superfamily of haem-thiolate proteins that are widely distributed across all living creatures. • The name given to this group of proteins because their reduced form binds with carbon monoxide to form a complex, which has maximum absorbance at 450 nm. • Depending upon the extent of amino acid sequence homology, the cytochrome P-450 (CYP) enzymes superfamily contains a number of isoenzymes, the relative amount of which differs among species and among individuals of the same species. • These isoenzymes are grouped into various families designated by Arabic numbers 1, 2, 3 (sequence that are greater than 40% identical belong to the same family), each having several subfamilies designated by Capital letter A, B, C, while individual isoenzymes are again allotted Arabic numbers 1.2,3 (e.g., CYP1A1, CYP1A2, etc.).
  • 26. ROLE OF CYP ENZYMES IN HEPATIC DRUG METABOLISM In human beings, of the 1000 currently known cytochrome P-450s, about 50 are functionally active. These are categorised into 17 families, out of which the isoenzymes CYP3A4 and CYP2D6 carry out biotransformation of largest number of drugs. RELATIVE HEPATIC CONTENT % DRUGS METABOLIZED OF CYP ENZYMES BY CYP ENZYMES CYP2E1 CYP2D6 7% 2% CYP 2C19 11% CYP 2C9 CYP 2C 14% CYP2D6 17% 23% OTHER 36% CYP 1A2 CYP 1A2 14% 12% CYP 3A4-5 CYP2E1 CYP 3A4-5 26% 5% 33%
  • 28. Participation of the CYP Enzymes in Metabolism of Some Clinically Important Drugs CYP Enzyme Examples of substrates 1A1 Caffeine, Testosterone, R-Warfarin 1A2 Acetaminophen, Caffeine, Phenacetin, R-Warfarin 2A6 17 -Estradiol, Testosterone 2B6 Cyclophosphamide, Erythromycin, Testosterone 2C-family Acetaminophen, Tolbutamide (2C9); Hexobarbital, S- Warfarin (2C9,19); Phenytoin, Testosterone, R- Warfarin, Zidovudine (2C8,9,19); 2E1 Acetaminophen, Caffeine, Chlorzoxazone, Halothane 2D6 Acetaminophen, Codeine, Debrisoquine 3A4 Acetaminophen, Caffeine, Carbamazepine, Codeine, Cortisol, Erythromycin, Cyclophosphamide, S- and R- Warfarin, Phenytoin, Testosterone, Halothane, Zidovudine
  • 29. 2. Reduction : Reduction Enzymes responsible for reduction of xenobiotics require NADPH as a cofactor. Substrates for reductive reactions include azo- or nitrocompounds, epoxides, heterocyclic compounds, and halogenated hydrocarbons: (a) Azo or nitroreduction by cytochrome P450; (b) Carbonyl (aldehyde or ketone) reduction by aldehyde reductase, aldose reductase, carbonyl reductase, quinone reductase (c) other reductions including disulfide reduction, sulfoxide reduction, and reductive dehalogenation.
  • 30. The acceptance of one or more electron(s) or their equivalent from another substrate. Reductive reactions, which usually involve addition of hydrogen to the drug molecule, occur less frequently than the oxidative reactions. Biotransformation by reduction is also capable of generating polar functional groups such as hydroxy and amino groups, which can undergo further biotrans-formation.  Many reductive reactions are exact opposite of the oxidative reactions (reversible reactions) catalysed cither by the same enzyme (true reversible reaction) or by different enzymes (apparent reversible reactions).  Such reversible reactions usually lead to conversion of inactive metabolite into active drug, thereby delaying drug removal from the body.
  • 32. 3. Hydrolysis : Esters, amides, hydrazides, and carbamates can be hydrolyzed by various enzymes.  The hydrolytic reactions, contrary to oxidative or reductive reactions, do not involve change in the state of oxidation of the substrate, but involve the cleavage of drug molecule by taking up a molecule of water. The hydrolytic enzymes that metabolise drugs are the ones that act on endogenous substances, and their activity is not confined to liver as they are found in many other organs like kidneys, intestine, plasma, etc. A number of drugs with ester, ether, amide and hydrazide linkages undergo hydrolysis. Important examples are cholinesters, procaine, procainamide, and pethidine.
  • 34. PHASE II REACTIONS  Phase II or conjugation (Latin, conjugatus = yoked together) reactions involve combination of the drug or its phase I metabolite with an endogenous substance to form a highly polar product, which can be efficiently excreted from the body.  In the biotransformation of drugs, such products or metabolites have two parts:  Exocon, the portion derived from exogenous compound or xenobiotic,  Endocon, the portion derived from endogenous substance.  Conjugation reactions have high energy requirement and they often utilise suitable enzymes for the reactions.
  • 35. The endogenous substances (endocons) for conjugation reactions are derived mainly from carbohydrates or amino acids and usually possess large molecular size.  They are strongly polar or ionic in nature in order to render the substrate water-soluble. The molecular weight of the conjugate (metabolite) is important for determining its route of excretion. High molecular weight conjugates are excreted predominantly in bile (e.g., glutathione exclusively, glucuronide mainly), while low molecular weight conjugates are excreted mainly in the urine. As the availability of endogenous conjugating substance is limited, saturation of this process is possible and the unconjugated drug/metabolite may precipitate toxicity.
  • 36. 1. Conjugation with glucuronic a./ Glucuronidation  Conjugation with glucuronic acid (glucuronide conjugation or glucuroni-dation) is the most common and most important phase II reaction in vertebrates, except cats and fish.  The biochemical donor (cofactor) of glucuronic acid is uridine diphosphate«-D-glucuronicacid (UDPGA) and the reaction is carried out by enzyme uridine diphosphate-glucuronyl transferase (UDP-giucuronyl transferase; glucuronyl transferase).  Glucuronyl transferase is present in microsomes of most tissues but liver is the most active site of glucuronide synthesis.
  • 37.  Glucuronidation can take place in most body tissues because the glucuronic acid donor UDPGA is present in abundant quantity in body, unlike donors involved in other phase II reactions.  In cats, there is reduced glucuronyl transferase activity, while in fish there is deficiency of endogenous glucuronic acid donor.  The limited capacity of this metabolic pathway in cats may increase the duration of action, pharmacological response and potential of toxicity of several lipid-soluble drugs (e.g., aspirin) in this species.
  • 38.  A large number of drugs undergo glucuronidation including morphine, paracetamol and desipramine. Certain endogenous substances such as steroids, bilirubin, catechols and thyroxine also form glucuronides.  Deconjugaiion process: Occasionally some glucuronide conjugates that are excreted in bile undergo deconjugation process in the intestine mainly mediated by β glucuronidase enzyme.  This releases free and active drug in the intestine, which may be reabsorbed and undergo entero-hepatic cycling.  Deconjugation is an important process because it often prolongs the pharmacological effects of drugs and/or produces toxic effects.
  • 39. 2. Conjugation with sulphate/ Sulphation:  Conjugation with sulphate (sulphate conjugation, sulphoconjugation orsulphation) is similar to glucuronidation but is catalysed by non-microsomal enzymes and occurs less commonly.  The endogenous donor of the sulphate group is 3'- phosphoadenosine-5'-phosphosulphate (PAPS), and enzyme catalysing the reaction is sulphotransferase
  • 40. The conjugates of sulphate are referred to as sulphate ester conjugates or ethereal sulphates. Unlike glucuronide conjugation, sulphoconjugation in mammals is less important because the PAPS donor that transfers sulphate to the substrate is easily depleted.  Capacity for sulphate conjugation is limited in pigs. However in cats, where glucuronidation is deficient, sulphate conjugation is important. Functional groups capable of forming sulphate conjugates include phenols, alcohols, arylamines, N- hydroxylamines and N-hydroxyamides.  Drugs undergoing sulphate conjugation include chloramphenicol, phenols, and adrenal and sex steroids.
  • 41. 3. Conjugation with methyl group/ Methylation :  Conjugation with methyl group (methyl conjugation or methylation) involves transfer of a methyl group (-CH3) from the cofactor S-adenosyl methionine (SAM) to the acceptor substrate by various methyl transferase enzymes.  Methylation reaction is of lesser importance for drugs, but is more important for biosynthesis (e.g., adrenaline, melatonin) and | Inactivation (e.g., histamine) of endogenous amines.  Occasionally, the metabolites formed are not polar or water- soluble and may possess equal or greater activity than the parent compound (e.g., adrenaline synthesised from noradrenaline).
  • 42. 4. Conjugation with glutathione and mercapturic acid formation.  Conjugation with glutathione (glutathione conjugation) and mercapturic acid formation is a minor but important metabolic pathway in animals.  Glutathione (GSH, G=glutathione and SH = active-SH group) is a tripeptide having glutamic acid, cysteine and glycine.  It has a strong nucleophilic character due to the presence of a -SH (thiol) group in its structure. Thus, it conjugates with electrophilic substrates, a number of which are potentially toxic compounds, and protects the tissues from their adverse effects.  The interaction between the substrate and the GSH is catalysed by enzyme glutathione- S-transferase, which is located in the soluble fraction of liver homogenates.  The glutathione conjugate either due to its high molecular weight is excreted as such in the bile or is further metabolised to form mercapturic acid conjugate that is excreted in the urine.
  • 43. 5. Conjugation with acetyl group/ Acetylation :  Conjugation with acetyl group (acetylation) is an important metabolic pathway for drugs containing the amino groups.  The cofactor for these reactions is acetyl coenzyme A and the enzymes are non-microsomal N-acetyl transferases, located in the soluble fraction of cells of various tissues.  Acetylation is not a true detoxification process because occasionally it results in decrease in water solubility of an amine and. thus, increase in its toxicity (e.g., sulphonamides).
  • 44.  Acetylation is the primary route of biotransformation of sulphonamide compounds. Dogs and foxes do not acetylate the aromatic amino groups due to deficiency of arylamine acetyltransferase enzyme.  Conjugation with amino acids : Conjugation with amino acids occurs to a limited extent in animals because of limited availability of amino acids. The most important reaction involves conjugation with glycine.  Conjugation with other amino acids like glutamine in man and ornithine in birds is also seen.  Examples of drugs forming glycine or glutamine conjugates are salicylic acid, nicotinic acid and cholic acid.
  • 45. Conjugation with thiosulphate : Conjugation with thiosulphate is an important reaction in the detoxification of cyanide. Conjugation of cyanide ion involves transfer of sulphur atom from the thiosulphate to the cyanide ion in presence of enzyme rhodancse to form inactive thiocyanate. Thiocyanate formed is much less toxic than the cyanide (true detoxification) and it is excreted in urine.
  • 48. INDUCTION OF METABOLISM  Administration of certain xenobiotics sometimes results in a selective increase in the concentration of metabolizing enzymes in both phase I and II metabolism, and thereby in their activities  Enzyme induction becomes important especially when polypharmacy involves drugs with narrow therapeutic windows, since the induced drug metabolism could result in a significant decrease in its exposure and therapeutic effects.  In addition, enzyme induction may cause toxicity, associated with increased production of toxic metabolites. Mechanisms of Induction  Stimulation of transcription of genes and/or translation of proteins, and/or stabilization of mRNA and/or enzymes by inducers, resulting in elevated enzyme levels.
  • 49.  Stimulation of preexisting enzymes resulting in apparent enzyme induction without an increase in enzyme synthesis (this is more common in vitro than in vivo).  In many cases, the details of the induction mechanisms are unknown.  TWO receptors have been identified for CYPlA1/2 and CYP4A1/2induction: (a) Ah (aromatic hydrocarbon) receptor in cytosol, which regulates enzyme (CYP1 A1 and 1A2) induction by polycyclic aromatic hydrocarbon (PAH)-type inducers; (b) Peroxisome proliferator activated receptor (PPAR), where hypolipidemic agents cause peroxisome proliferation in rats (CYP4A1 and 4A2);-humans have low PPAR and show no effects from hypolipidemic agents.
  • 50. Characteristics of Induction  Induction is a function of intact cells and cannot be achieved by treating isolated cell fractions such as microsomes with inducers.  Evaluation of enzyme induction is usually conducted in ex vivo experiments, ie., treating animals in vivo with potential inducers and measuring enzyme activities in vitro or in cell-based in vitro preparations such as hepatocytes, liver slices, or cell lines.  Recent studies have demonstrated that primary cultures of hepatocytes can be used for studying the inducibility of metabolizing enzymes such as P450 under certain incubation conditions  Enzyme induction is usually inducer-concentration–dependent. The extent of induction increases as the inducer concentration increases; however, above certain values, induction starts to decline.  In general, inducers increase the content of endoplasmic reticulum within hepatocytes as well as liver weight.  In some cases, an inducer induces enzymes responsible for its own metabolism (so-called “autoinduction”).
  • 51. Induction of Drug Metabolising Enzymes  Several drugs and chemicals have ability to increase the drug metabolising activity of enzymes called as enzyme induction.  These drugs known as enzyme inducers mainly interact with DNA and increase the synthesis of microsomal enzyme proteins, especially cytochrome P-450 and glucuronyl transferase.  As a result, there is enhanced metabolism of endogenous substances (e.g., sex steroids) and drugs metabolised by microsomal enzymes. Some drugs (e.g., carbamazepine and rifampicin) may stimulate their own metabolism, the phenomenon being called as auto-induction or self induction.
  • 52. Since different cytochrome P450 isoenzymes are involved in the metabolism of different drugs, enzyme induction by one drug affects metabolism of only those drugs, which are substrate for the induced isoenzyme. However, some drugs like Phenobarbitone may affect metabolism of a large number of drugs because they induce isoenzymes like CYP3A4 and CYP2D6 which act on many drugs. Enzyme inducers are generally lipid-soluble compounds with relatively long plasma half-lives. Repeated administration of inducers for a few days (3 to 10 days) is often required for enzyme induction, and on stoppage of drug administration, the enzymes return to their original value over 1 to 3 weeks. Non-microsomal enzymes are not known to be induced by any drug or chemical.
  • 54. Clinical importance of enzyme induction  It reduces efficacy and potency of drugs metabolised by these enzymes.  It reduces plasma half-life and duration of action of drugs.  It enhances drug tolerance.  It increases drug toxicity by enhancing concentration of metabolite, if metabolite is toxic.  It increases chances of drug interactions.  It alters physiological status of animal due to altered metabolism of endogenous compounds like sex steroids.
  • 55. Inhibition of Drug Metabolising Enzymes  Contrary to metabolising enzyme induction, several drugs or chemicals have the ability to decrease the drug metabolising activity of certain enzymes called as enzyme inhibition.  Enzyme inhibition can be either non-specific of microsomal enzymes or specific of some non-microsomal enzymes (e.g., monoamine oxidase, cholinesterase and aldehyde dehydrogenase).  The inhibition of hepatic microsomal enzymes mainly occurs due to administration of hepatotoxic agents, which cause either rise in the rate of enzyme degradation (e.g., carbon tetrachloride and carbon disulphide) or fall in the rate of enzyme synthesis (e.g., Puromycin and Dactinomycin).
  • 56.  Nutritional deficiency, hormonal imbalance or hepatic dysfunction, etc.also inhibit microsomal enzymes indirectly.  Inhibition of non-microsomal enzymes with specific function usually results when Structurally similar compounds compete for the active site on the enzymes.  Such an inhibition is usually rapid (a single dose of inhibitor may be sufficient) and clinically more important than the non- specific microsomal enzyme inhibition.  Enzyme inhibition generally results in depressed metabolism of drugs. As a result, the plasma hall-life, duration of action, and efficacy as well toxicity of the object drug (whose metabolism has been inhibited) are significantly enhanced.
  • 57.  In case the drug undergoes hepatic first-pass effect, the bioavailability and toxicity Of the drug will be markedly increased in presence of enzyme inhibition. Enzyme inhibition may also produce undesirable drug interactions.  In therapeutics, some specific enzyme inhibitors like monoamine oxidase inhibitors, cholinesterase inhibitors and angiotensin converting enzyme (ACE) inhibitors are purposely used for producing desirable pharmacological actions
  • 58. Inducing Agents  In general, enzyme inducers are lipophilic at physiological pH and exhibit relatively long t 1/2 with high accumulation in the liver. Different classes of enzyme inducers. 1. Barbiturates: Phenobarbitone, Phenobarbital. 2. Polycyclic aromatic hydrocarbons (PAH): 3-methylcholanthrene (3-MC), 2,3,7,8,-tetrachlorodibenzo-p-dioxin (TCDD), β-naphthoflavone β ( -NF). 3. Steroids: Pregnenalone 16-α -carbonitrile (PCN), Dexamethasone. 4. Simple hydrocarbons with aliphatic chains: Ethanol (chronic), Acetone, 5. Hypolipidemic agents: Clofibrate, lauric acids. 6. Macrolide antibiotics: Triacetyloleandomycin (TAO). 7. A wide variety of structurally unrelated compounds: e.g., Antipyrine, Carisoniazid. Bamazepine, Phenytoin, and Rifampicin
  • 63. EXTRAHEPATIC METABOLISM  Most tissues have some metabolic activity; however, quantitatively the liver is by far the most important organ for drug metabolism. Important organs for extrahepatic metabolism include the intestine (enterocytes and intestinal microflora), kidney, lung, plasma, blood cells, placenta, skin, and brain.  In general, the extent of metabolism in the major extrahepatic drug-metabolizing organs such as the small intestine, kidney, and lung is approximately 10–20% of the hepatic metabolism.  Less than 5% of extrahepatic metabolism compared to hepatic metabolism can be considered low with negligible pharmacokinetic implications
  • 64. First-Pass Effect/First-Pass Metabolism  First-pass effect (first-pass metabolism or pre-systemic metabolism) may be defined as the loss of drug through biotransformation before it enters systemic circulation.  This may occur during passage of drug for first time (therefore called first-pass effect/metabolism) through intestine or liver after oral administration.  Intestinal first-pass effect: In this type, drugs are metabolised in the gastrointestinal tract by enzymes present in either gut mucosa or gut lumen before they are absorbed  Recent studies have indicated that P450 isoforms such as CYP2C19 and 3A4 in enterocytes might play an important role in the presystemic intestinal metabolism of drugs and the large interindividual variability in systemic exposure after oral administration  The cytochrome P450 content of the intestine is about 35% of the hepatic content in the rabbit, but accounts for only 4% of the hepatic content in the mouse. Cytochrome P450 levels and activities are highest in the duodenum near the pyrolus, and then decrease toward the colon  A similar trend in regional activity levels along the intestine has been observed for glucuronide, sulfate, and glutathione conjugating enzymes.
  • 65.  Microorganisms present in the GI tract also inactivate some drugs. Such drugs are not suitable by oral administration due to poor bioavailability (e.g., catecholamines).  Hepatic first-pass effect: In this type, drugs are suitably absorbed across the GI tract and enter portal circulation, but they are rapidly and significantly metabolised during the first passage through the liver.  (Normally, when a drug is absorbed across GI tract, it first enters the portal vein and passes through liver before it reaches the systemic circulation).  Such drugs are also not/less suitable by oral administration due to their poor bioavailability. Examples of drugs undergoing significant hepatic first-pass effect include Propranolol, Lignocaine and Nitro-glycerine.
  • 66. The rate and extent of first-pass intestinal metabolism of a drug after oral administration are dependent on various physiological factors 1. Site of absorption: If the absorption site in the intestine is different from the metabolic site, first-pass intestinal metabolism of a drug may not be significant. 2. Intracellular residence time of drug molecules in enterocytes: The longer the drug molecules stay in the enterocytes prior to entering the mesenteric vein, the more extensive the metabolism. 3. Diffusional barrier between splanchnic bed and enterocytes: The lower the diffusibility of a drug from the enterocytes to the mesenteric vein, the longer its residence time. 4. Mucosal blood flow: Blood in the splanchnic bed can act as a sink to carry drug molecules away from the enterocytes, which reduces intracellular residence time of drug in the enterocytes
  • 67. Renal Metabolism  In addition to physiological functions of homeostasis in water and electrolytes and the excretion of endogenous and exogenous compounds from the body, the kidneys are the site of significant biotransformation activities for both phase I and phase II metabolism.  The renal cortex, outer medulla, and inner medulla exhibit different profiles of drug metabolism, which appears to be due to heterogeneous distribution of metabolizing enzymes along the nephron.  Most metabolizing enzymes are localized mainly in the proximal tubules, although various enzymes are distributed in all segments of the nephron  The pattern of renal blood flow, pH of the urine, and the urinary concentrating mechanism can provide an environment that facilitates the precipitation of certain compounds, including metabolites formed within the kidneys.  The high concentration or crystallization of xenobiotics and/or their metabolites can potentially cause significant renal impairment in specific regions of the kidneys.
  • 68. Metabolism in Blood  Blood contains various proteins and enzymes.  As metabolizing enzymes, esterases, including cholinesterase, arylesterase, and carboxylesterase, have the most significant effects on hydrolysis of compounds with ester, carbamate, or phosphate bonds in blood .  Esterase activity can be found mainly in plasma, with less activity in red blood cells.  Plasma albumin itself may also act as an esterase under certain conditions.  For instance, albumin contributes about 20% of the total hydrolysis of aspirin to salicylic acid in human plasma.  The esterase activity in blood seems to be more extensive in small animals such as rats than in large animals and humans. Limited, yet significant monoamine oxidase activities can be also found in blood.