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WELCOME

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Presented ByArchana S NairM Pharm Part 1Pharmaceutics

RENAL CLEARANCE

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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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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

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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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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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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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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 flowCa= incoming drug concentrationCv= outgoing drug concentration

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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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MODEL INDEPENDENT METHODS Clearance may be determined directly from the plasma – time

concentration curve by

D0= doseC(t)= unknown function that describes the declining plasma drug concentration.

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MODEL INDEPENDENT METHODSCompartment 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

?V Cp

Elimination

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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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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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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.

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 0Below 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, PAH15

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DETERMINATIONOF RENAL CLEARANCE

GRAPHICAL METHODS

MODEL INDEPENDENT METHODS

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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 concentrationCp

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GRAPHICAL METHODS

Rate of drug slope = renal clearance excretion

Plasma level(Cp)

A

B

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GRAPHICAL METHODS

Multiplying both sides by Cp gives

By rearranging and integrating

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GRAPHICAL METHODS

Drug excreted Slope= ClR

in urine(Du)Slope= ClR

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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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MODEL INDEPENDENT METHODS

Advantage

• Rapid and easily obtainable

estimates of drug clearance.

Disadvantage

• Calculation does not reflect non linear changes in the

clearance rates.

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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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CREATININE CLEARANCE Determination of serum creatinine level.

Direct method for determining creatinine clearance

Normal value – 120 - 130 ml/min.

Males

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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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FACTORS AFFECTING RENAL EXCRETION OR RENAL CLEARANCE1. Physicochemical properties of drug2. Plasma concentration of drug3. Distribution and binding characteristics of

drug 4. Urine pH5. Blood flow to the kidney6. Biological factors7. Drug interactions8. Disease state

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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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PLASMA CONCENTRATION OF THE DRUG

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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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BLOOD FLOW TO KIDNEYS & BIOLOGICAL FACTORSBLOOD 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.

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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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DISEASE STATEDisease 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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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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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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