methods for determining renal clearance, factors affecting renal clearance

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2. Presented By
Archana S Nair
M Pharm Part 1
Pharmaceutics
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3. CONTENTS
 Introduction.
 Clearance models.
 Physiologic or organ clearance.
 Model independent methods.
 Renal clearance.
 Comparison of drug excretion methods.
 Relationship between renal clearance values & mechanism of
clearance.
 Graphical method & model independent method.
 Creatinine clearance, total body clearance.
 Factors affecting renal excretion or renal clearance.
 References
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4. INTRODUCTION
DRUG CLEARANCE
 Pharmacokinetic term
 Hypothetical volume of body fluids containing drug from which drug is
removed or cleared completely in a specific period of time.
 Unit-ml/min or litre/hour
 Total body clearance is the sum of individual clearances by all eliminating
organs.
 Body clearance= keVD +klVD +kmVD = kVD 4

5. INTRODUCTION
 ClT is the rate of drug elimination divided by the plasma drug
concentration
ClT = elimination rate
plasma drug concentration(Cp)
Cl T = dDE /dt = mL/min
Cp
DE = amount of drug eliminated
dDE /dt = rate of elimination
Elimination rate = dDE =Cp ClT
dt
First order elimination rate , dDE/dt=kCpVD
ClT = kCpVD = kVD
Cp
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6. CLEARANCE MODELS
 Calculation from k and VD assumes a model.
 Estimated directly from plasma concentration time curve does not
assume any model.
•Compartment model
•Physiologic model
•Model independent
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7. PHYSIOLOGIC /ORGAN CLEARANCE
 Clearance may be calculated for any organ involved in the irreversible
removal of drug from the body.
 Kidneys and liver.
 Physiologic models are based on drug clearance through individual organs
or tissue groups.
 Fraction of blood volume containing drug that flows through the organ and
is eliminated of drug per unit time.
 Clearance = blood flow (Q) × extraction ratio (ER)
 ER = Ca-Cv
Ca
 Cl = Q(Ca – Cv)
Ca
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8. PHYSIOLOGIC /ORGAN CLEARANCE
 Blood flow rate and the ability of organ to eliminate the drug.
 Require invasive techniques to obtain measurements of
blood flow and extraction ratio.
Q Ca Q Cv
elimination drug
Elimination
organ
Q= blood flow
Ca= incoming drug concentration
Cv= outgoing drug concentration
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9. MODEL INDEPENDENT METHODS
 Plasma drug concentration time curve.
 Calculate certain pharmacokinetic parameters - clearance and
bioavailability.
 Advantages–
 No assumption for a specific compartment model is required to
analyze the data.
 The volume of distribution and the elimination rate constant
need not be determined.
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10. MODEL INDEPENDENT METHODS
 Clearance may be determined directly from the plasma – time
concentration curve by
D0= dose
C(t)= unknown function that
describes the declining plasma drug
concentration.
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11. MODEL INDEPENDENT METHODS
Compartment model
static volume and first-order elimination is assumed plasma flow is not
considered. ClT = k VD
Physiologic model
Qca Q Cv
ClT=Q ER
Model independent
? k
VD Cp
Cp
Elimination
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12. RENAL CLEARANCE
 Volume of plasma that is cleared of drug per unit of time through the
kidney.
 Constant fraction of VD in which the drug is contained that is excreted by
the kidney per unit of time.
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13. RENAL CLEARANCE
 Consider the mass balance of drug cleared by the kidney and ultimately
excreted in urine.
 Rate of drug passing through kidney = rate of drug excreted in urine
= renal clearance = plasma drug concentration
= rate of urine flow = urine drug concentration
excretion rate
=
•
Cp
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14. COMPARISON OF DRUG EXCRETION
METHODS
 ClR = Rate of (filtration + secretion – reabsorption)
Plasma drug concentration.
 Renal clearance ratio = ClR of drug
ClR of creatinine.
 Actual clearance is not obtained by direct measurement.
 Compared to that of standard reference standard such as inulin.
 Clearance ratio indication for the mechanism of renal excretion
of the drug.
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15. RELATIONSHIP BETWEEN RENAL CLEARANCE
VALUES & MECHANISM OF CLEARANCE
Renal
clearance(ml/min)
Renal clearance ratio Mechanism of
renal clearance
Examples
0(least value) 0 Drugs filtered and
reabsorbed
Glucose
<130 Above 0
Below 1
Drugs filtered and
reabsorbed partially
Lipophilic drugs
130(GFR) 1 Drug is filtered only Creatinine, insulin
>130 >1 Drug filtered as well
as secreted actively
Polar, ionic drugs
650(highest value) 5 Clearance equal to
renal plasma flow
rate
Iodopyracet, PAH
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DETERMINATIONOF RENAL
CLEARANCE
GRAPHICAL METHODS
MODEL INDEPENDENT METHODS

17. GRAPHICAL METHODS
 Slope of the curve obtained by plotting rate of drug excretion in
urine (dDu/dt) against Cp.
 For a drug that is excreted rapidly, dDu/dt is large, the slope is
steeper, and clearance is greater.
 For a drug that is excreted slowly through the kidney , the slope is
smaller.
 Clr = Urinary drug excretion rate = dDu/dt
Plasma drug concentration Cp
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18. GRAPHICAL METHODS
Rate of drug slope = renal clearance
excretion
Plasma level(Cp)
A
B
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19. GRAPHICAL METHODS
Multiplying both sides by Cp gives
By rearranging and integrating
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20. GRAPHICAL METHODS
Drug excreted Slope= ClR
in urine(Du)
Slope= ClR
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21. MODEL INDEPENDENT METHODS
 Nongraphical calculation from the knowledge of
, FD0,
If total amount of drug excreted in urine ( ) has been
obtained, then clearance is calculated by
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22. MODEL INDEPENDENT METHODS
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Advantage
• Rapid and easily obtainable
estimates of drug clearance.
Disadvantage
• Calculation does not reflect
non linear changes in the
clearance rates.

23. CREATININE CLEARANCE
 Volume of blood plasma that is cleared of creatinine per unit time and is a
useful measure for approximating GFR.
 Used to determine renal function.
 Endogenous amine produced as a result of muscle catabolism.
 Excreted unchanged in the urine by glomerular filtration only.
 Advantage –
It can be correlated to steady-state concentration of creatinine in plasma and
needs no collection of urine.
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24. CREATININE CLEARANCE
 Determination of serum creatinine level.
 Direct method for determining creatinine clearance
 Normal value – 120 - 130 ml/min.
Males
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25. TOTAL BODY CLEARANCE
 The sum of individual clearances by all eliminating organs
 ClT = k VD
 ClR= ke VD
 ClH = km VD
 ClT = ClR + ClH
 k= ke+km
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26. FACTORS AFFECTING RENAL EXCRETION OR
RENAL CLEARANCE
1. Physicochemical properties of drug
2. Plasma concentration of drug
3. Distribution and binding characteristics of drug
4. Urine pH
5. Blood flow to the kidney
6. Biological factors
7. Drug interactions
8. Disease state
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27. FACTORS AFFECTING RENAL EXCRETION
OR RENAL CLEARANCE
• Physicochemical properties of drug
 Molecular size
• Drugs with Mol.wt <300, water soluble are excreted in kidney.
• Mol.wt 300 to 500 Dalton are excreted both through urine and bile.
• Drugs or metabolites > 500 Daltons, mainly in bile, excreted in urine
to a lesser extent.
 pKa
excretion of unchanged drug is inversely related to its lipophilicity.
 Stereochemical nature of drug
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28. PLASMA CONCENTRATION OF THE
DRUG
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29. DISTRIBUTION AND BINDING
CHARACTERISTICS OF THE DRUG
 Drug with larger Vd poorly excreted in urine.
 Drugs bound to plasma protein cannot be filtered through the
glomerulus.
 ClR = Urine drug concentration × Urine flow rate
Plasma drug concentration
 F u = Cu / C
 ClR = F u × Urine flow rate
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30. BLOOD FLOW TO KIDNEYS & BIOLOGICAL
FACTORS
BLOOD FLOW TO THE KIDNEYS
 Increased perfusion increases contact of drug with the secretory
sites and enhances their elimination.
BIOLOGIC FACTORS
 Renal excretion is approximately 10% lower in females than in
males.
 Renal function of newborns is 30-40% less in comparison to adults
and attains maturity between the age 2.5 to 5 months of age.
 In old age, GFR is reduced. 30

31. DRUG INTERACTIONS
Alteration in P-D binding gentamicin induced nephrotoxicty by
furosemide.
Alteration of urine pH Acidification of urine with ammonium
chloride, methionine or ascorbic acid enhances the excretion of basic
drug.
 Alkalinisation of urine with citrates, tartarates promote excretion of acidic
drugs.
Competition for active secretion
 Phenylbutazone competes with hydroxyhexamide for active secretion and
thus prolongs its action.
Forced diuresis- all diuretics increase elimination.
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32. DISEASE STATE
Disease state –renal impairment.
 Renal dysfunction
 Impairs the elimination of drugs.
 Causes of renal failure are hypertension, diabetes mellitus, hypovolemia,
nephrotoxic agents like aminoglycosides, phenacetin.
 Uremia
 Characterised by impaired glomerular filtration and accumulation of fluids
and protein metabolites.
 Drug accumulation and toxicity may result.
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33. CONCLUSION
 The clearance concept was first introduced to describe renal
excretion of endogenous compounds in order to measure the
kidney function.
 The term is now applied to all organs involved in drug
elimination like liver, lungs, biliary system etc.
 Clearance values gives useful estimates regarding a lot of
disease states.
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34. REFERENCES
 Shargel L, Susanna Wu-pong, Andrew BC. Applied
biopharmaceutics and pharmacokinetics :drug
elimination and clearance,. 5th ed. 2009. p.:131-53.
 Brahmankar DM , Jaiswal BS . Biopharmaceutics and
pharmacokinetics: a treatise. 2nd ed. Delhi: Vallabh
prakasan; 2013. p.204-09.
 www.austincc.edu/emeyerth/clearancehtm.htm
 www.mhhe.com/biosci/ap/vander/urinary/reang9.mhtm
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