4. IMPLICATIONS FOR DRUG METABOLISM 1. Termination of drug action 2. Activation of prodrug 3. Bioactivation and toxication 4. Carcinogenesis 5. Tetratogenesis www.freelivedoctor.com
5. Termination of Drug Action www.freelivedoctor.com tropic acid and tropine atropine propranolol hydroxypropranolol (active) (active)
6. Termination of Drug Action Conversion of drug to active metabolite to active metabolite to inactive metabolite www.freelivedoctor.com
8. Inactive Terfenadine is Converted to its Active Metabolite Fexofenadine terfenadine fexofenadine activation of prodrug www.freelivedoctor.com
9.
10. Small Amounts of Acetaminophen is Converted to the Reactive Metabolite N-Acetylbenzoquinoneimine Bioactivation of acetaminophen; under certain conditions, the electrophile N-acetylbenzoquinoneimine reacts with tissue macromolecules, causing liver necrosis. bioactivation www.freelivedoctor.com
23. First Order Metabolism v = Vmax [C] Km + [C] When Km >>> [C], then v = Vmax [C] , Km and v [C] Metabolism of the drug is a first order process. A constant fraction of the remaining drug is metabolized per unit time. Most drugs are given at concentrations smaller than the Km of the enzymes of their metabolism. A drug may be given in doses that produce blood concentrations less than the Km of the enyzme for the drug. www.freelivedoctor.com
25. Zero Order Metabolism v = Vmax [C] K m + [C] When [C] >>> Km, then v = Vmax [C] , [C] and v = Vmax Metabolism of the drug is a zero order process. A constant amount of the remaining drug is metabolized per unit time. Phenytoin undergoes zero order metabolism at the doses given. A drug may be given in doses that produce blood concentrations greater than the Km of the enyzme for the drug. www.freelivedoctor.com
29. Phase I Metabolism R R OH R R COOH R R SH R R NH 2 Polar groups are exposed on or introduced to a molecule www.freelivedoctor.com
30. Phase I Reactions OXIDATION REDUCTION HYDROLYSIS www.freelivedoctor.com
31. Phase II Metabolism A molecule endogenous to the body donates a portion of itself to the foreign molecule www.freelivedoctor.com D+ ENDO X D X + ENDO
65. Codeine is a Substrate of CYP2D6 Consider the variation in codeine’s metabolism among PM, IM, EM, UM individuals -CH 3 (methyl morphine) www.freelivedoctor.com
71. Nonmicrosomal Oxidations Alcohol dehydrogenation is conducted by the enzyme alcohol dehydrogenase (cytosolic) Aldehyde dehydrogenation is conducted by the enzyme aldehyde dehydrogenase (cytosol and mitochondria) Xanthine oxidation is conducted by the cytosolic enzyme xanthine oxidase. Diamine oxidase (cytosolic) oxidizes histamine and diamines such as cadaverine and putrescine. Monoamine oxidation is conducted by mitochondrial monoamine oxidase (norepinephrine, epinephrine, dopamine and serotonin are endogenous substrates. www.freelivedoctor.com
96. D+ ENDO X D X + ENDO PHASE 2 METABOLISM A molecule endogenous to the body donates a portion of itself to the foreign molecule www.freelivedoctor.com
99. Uridine-5’- -D-glucuronic Acid The microsomal enzyme glucuronyl transferase conducts the donation of glucuronic acid from the endogenously synthesized UDPGA to various substrates to form glucuronide conjugates. Examples of such substrates are morphine and acetaminophen. www.freelivedoctor.com
110. 3’-Phosphoadenosine-5’-phosphosulfate (PAPS) The cytosolic enzyme sulfotransferase conducts the donation of sulfate from the endogenously synthesized PAPS to various substrates to form sulfate conjugates. An example of such substrate is acetaminophen. www.freelivedoctor.com
111. Sulfate Conjugation of p -Hydroxyacetanilid PAP: 3’-phosphoadenosine- 5’-phosphate www.freelivedoctor.com
116. Acetyl CoA Various acetylases, for examples, choline acetylase and N-acetyl transferase, all soluble enzymes, conduct the transfer of the acetyl group of acetyl CoA to various substrates. For example, N-acetylation of isoniazid. Genetic polyporphism occurs with N-acetyltransferase. www.freelivedoctor.com
122. S-Adenosylmethionine Cytosolic enzymes such as catechol-O-methyl transferase (COMT) and phenylethanolamine-N-methyl transferase (PNMT) conducts the donation of the methyl group from the endogenously synthesized SAM to various substrates to form methylated conjugates. Norepinephrine is N-methylated by PNMT to form epinephrine. Norepinephrine, epinephrine, dopamine, and L-DOPA are O-methylated by COMT. www.freelivedoctor.com
127. S-Methylation of 6-Mercaptopurine TPMT - thiopurinemethyltransferase; some individuals are deficient in this enzyme that is critically important for the metabolism of this agent www.freelivedoctor.com
131. Multiple Metabolic Pathways Exist for Aspirin’s Metabolism Hydolysis of aspirin produces salicyclic acid, as seen in the next slide www.freelivedoctor.com
132. Salicyluric Acid is the Glycine Conjugate of Aspirin Salicyluric acid, the glycine conjugate of salicyclic acid, is the main metabolite of aspirin. Approximately 76% of aspirin is metabolized through amino acid conjugation. www.freelivedoctor.com
141. ACETAMINOPHEN AND ITS PHASE II METABOLITES The sulfate and glucuronide conjugates of acetaminophen are the major metabolites. High doses of acetaminophen can exhaust the metabolic pathways that produce these conjugates, allowing more of the parent drug to undergo the phase I metabolic pathway which is involved in bioactivation and toxication. www.freelivedoctor.com
143. ACETAMINOPHEN AND ITS PHASE I METABOLITES- pt2 The minor metabolite (4% of acetaminophen), N-hydroxyacetaminophen , is always produced by microsomal cytochrome P450. It rearranges to the electrophile N-acetylbenzoquinoneimine, which in turn reacts with the sulfhydryl group of glutathione. Acetaminophen mercapturic acid is the final metabolite. If tissue glutathione stores are depleted as a result of fasting, intake of excessive doses of acetaminophen or through induction of CYP2E1 as a result of chronic intake of ethanol, the quinone interacts with nucleophilic sites of cellular macromolecules, such as proteins. Liver necrosis is the result. Regular intake of acetaminophen during fasting or chronic ethanol intake should be avoided. N-acetylcysteine is the antidote for acetaminophen poisoning. It reacts with the electrophile. A small amount of acetaminophen is reported to undergo deacetylation to the phase 1 metabolite p -aminophenol. www.freelivedoctor.com
146. N-Hydroxylation of AAF N-Hydroxylation of AAF is the first metabolic step towards the development of a carcinogenic agent www.freelivedoctor.com
147. Further Metabolism of N-HydroxyAAF Produces Cancer N-HydroxyAAF undergoes phase II metabolism to the ultimate carcingogen. The glucuronide pathway is also involved in carcinogenesis www.freelivedoctor.com
