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CONCEPT OF CLEARANCE PRESENTATION BY RAVULAPALLI CHIRANJEEVI 1ST M.Pharmacy(Pharmaceutics) Vikas college of Pharmacy

1Concept of clearanceRenal ClearanceFactors affecting renal excretion or renal clearanceOrgan clearanceHepatic clearance

22CONCEPT OF CLEARANCE

The clearance concept was first introduced to describe renal excretion of endogenous compounds in order to measure the kidney function. The clearence applied to all organs involved in drug elimination such as liver ,lungs, the biliary system and refer to as hepatic clearence, pulmonary clearence.The sum of individual clearances by all eliminating organs is called as total body clearance or total systemic clearance. It is sometimes expressed as a sum of renal clearance and nonrenal clearance.3Clearance is defined as the hypothetical volume of body fluids containing drug from which the drug is removed or cleared completely in a specific period of time.

It is expressed in ml/min and is a constant for any given plasma drug concentration. Clearance (Cl) = Elimination rate Plasma drug concentration

4TOTAL BODY CLEARENCE5Elimination of a drug from the body involes process occuring inkidney,liver,lungs and other eliminating orgns.It can be estimated by dividing the rate of elimination by each organ with the concentration of drug thusHEPATIC CLEARENCE ClH = rate of elimination by liver C RENAL CLEARENCE ClR = rate of elimnination by kidney C

OTHER ORGAN CLEARANCE Clothers = rate of elimination by other organs CTOTAL BODY CLEARENCE ClT = ClR + ClH + Clothers According to earlier definition

6 dX/dt CIT = -------------- C

KE X CIT = -------------- C

CIT = KE. Vd

CIT = 0.693. Vd / t1/2 7Organ Clearance: The best way of understanding clearance is at individual organ level. Such a physiologic approach is advantageous in predicting and evaluating the influence of pathology, blood flow, P-D binding, enzyme activity, etc. on drug elimination.

At an organ level, the rate of elimination can be written as:Rate of elimination by an organ = Rate of presentation to the organ - Rate of exit from the organ

Rate of presentation = Organ blood flow Entering concentration(input) = Q. Cin

Rate of exit (output) = Organ blood flow Exiting concentration = Q. Cout8Rate of elimination = Q.Cin - Q,Cout

(also called as rate of extraction) = Q (Cin Cout)

Division of above equation by concentration of drug that enters the organ of elimination Cin yields an expression for clearance of drug by the organ under consideration. Thus:

Rate of extraction = Clorgan = Q (Cin Cout) = Q.ER Cin Cin

where, ER = (Cin- Cout)/Cin is called as extraction ratioIt has no units and its value ranges from zero (no elimination) to one (complete elimination).9Based on ER values, drugs can be classified into 3 groups:-drugs with high ER (above 0.7)-drugs with intermediate ER (between 0.7 to 0.3) and-drugs with low ER (below 0.3).

ER is an index of how efficiently the eliminating organ clears the blood flowing through it of drug. F = 1-ER10Hepatic Clearance:

For certain drugs, the nonrenal clearance can be assumed as equal to hepatic clearance CIH. It is given as:

CIH= CIT- CIR

An equation parallel to equation can also be written for hepatic clearance:

CIH = QH.ERH

where, QH = hepatic blood flow (about 1.5 liters/min), and

ERH = hepatic extraction ratio.11The hepatic clearance of the drugs can be divided into two groups1.Drugs with hepatic blood flow rate-limited clearance2.Drugs with intrinsic capacity limited clearance

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1.Drugs with hepatic blood flow rate-limited clearance: When ERHis one, ClH approaches its maximum value i.e.hepatic blood flow in such situation,hepatic clearance is said to be perfusion rate limited.Alteration in hepatic blood flow significantly affects the elimination of drugs with high ERHeg;:propranolol,lidocaine,such drugs are removed from the blood as rapidly as they are presented to the liver.Indocyanine green is so rapidly eliminated by human liver that its clearance is often used as an indicator of hepatic blood flow rate.

F=1- ERH= AUCoral

AUCI.V.Intrinsic capacity clearance: Denoted as ,it is defined as the inherent ability of an organ to irreversibly remove a drug in the absence of any flow limitations.Its depends upon the hepatic enzyme activity.Drugs with low and with elimination by metabolism are greatly affected by changes in enzyme activity.Hepatic clearance of such drugs are said to be capacity limited.Eg:theophylline.Hepatic clearance of the drugs with low ER is independent of blood flow rate but sensitivity to changes in protein binding.HEPATIC AND RENAL EXTRACTION RATIO OF SOME DRUGS AND METABOLITES:EXTRACTION RATIO:

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High IntermediateLowHepatic extractionPropranololLidocaineNitrro glycerineAspirinCodeineQuinidine

DiazepamPhenobarbitolphenytoinRenal extractionSome penicillins,several sulphatesProcainamide,cimetidineDigoxinAtenololtetracycline14Renal Clearance (CIR): It can be defined as the volume of blood or plasma which is completely cleared of the unchanged drug by the kidney per unit time. It is expressed mathematically as: CIR = Rate of urinary excretion Plasma drug concentration15Physiologically speaking, renal clearance is the ratio of "sum of rate of glomerular filtration and active secretion minus rate of reabsorption to "plasma drug concentration C".

CIR = Rate of filtration + Rate of secretion - Rate of reabsorption C16Factors affecting renal excretion or renal clearance

1. Physicochemical properties of the drug.Eg:molecular size,pka2. Plasma concentration of the drug.3. Distribution and binding characteristics of the drug4. Urine pH5. Blood flow to the kidneys6. Biological factors7. Drug interactions

17Physicochemical Properties of the DrugImportant physicochemical factors affecting renal excretion of a drug are - molecular size, pKa and lipid solubility.

Plasma Concentration of the Drug1.Drug excreted by filtretion only2.Drug filtered and actively reabsorbed3.Drug filtered as well actively secretedPlasma Concentration

18REFERENCE:Biopharmaceutics and pharmacokinetics D.M.BRAHMANKAR SUNIL B. JAISWALBiopharmaceutics and clinical pharmacokinetics MILO GIBALDIApplied biopharmaceutics and pharmacokinetics LEON SHARGEL19I THANK TO BELOWED STAFF AND MY ROOM MATES

BE PROUD TO BE A PHARMACIST20