Lecture 6 - Drug Excretion 15 Sep 2006

Drug excretion Drugs can be excreted by several routes: kidneys (urine) the intestinal tract (bile and feces) the lungs (exhaled air) breast milk sweat

Excretions in the urine and feces are the most important routes of drug elimination.

Drug clearance Clearance is the ability of the body or its organs of elimination (usually the kidneys and the liver) to remove drug from blood.

Clearance is expressed as a volume per unit of time (usually ml/minute)

BLOOD + DRUG

KIDNEYS

DETECTOR CLEAN BLOOD 30 ml/min

LIVER BLOOD

CLEAN BLOOD 50 ml/min

Clearance is not the amount of drug removed from the body Clearance represents the volume of blood which is completely cleared from drug in a given period of time.

Total clearance is the sum of clearance by different organs like the kidneys, the liver and others

Clearance as through the kidneys and metabolism in the liver are the major routes: Clearance (total) = Clearance (hepatic) + clearance (renal) + Clearance (others) A decrease in the function of an organ of elimination is most significant when that organ serves as the primary route of drug elimination.

Rate of elimination of drug Rate of elimination is the number of mg of drug eliminated from the body per time (ml/minute). Rate of elimination depends on the concentration of drug in blood and clearance: Rate of elimination (mg/min) = Plasma drug concentration (mg/ml) * Clearance (ml/min)

Example: Plasma drug concentration = 10 mg/ml Clearance = 8 ml/min Rate of elimination = 80 mg/ml The amount of drug eliminated in one minute is 80 mg.

First-order kinetics Experimental data for many drugs show that the rates of drug elimination, absorption, and distribution are directly proportional to concentration.

(Half-life (t1/2 The time it takes for plasma drug concentration to be increased or reduced by 50%

t1/2 is constant for a drug that follows first-order kinetics.

Amount of Drug Remaining In Body or Cp

t=0

1 t1/2

2 t1/2

3 t1/2

4 t1/2

Drug Discontinued % 0 Eliminated

50

75

87.5

93.75

t=0

1 t1/2 2 t1/2 Maintainance Dose of Drug initiated % Accumulation 50 or % of steady State achieved

75

3 t1/2

87.5

4 t1/2

93.75

8

Cpss =8

Cp

100

Plasma concentration of drug (arbitrary units) 100 100 mg injected

50

0

t 1/2 Injection of drug

Plasma concentration of drug (arbitrary units)

100

50

100 mg injected

50 mg injected

0 Half-life (t1/2) of drug t 1/2 Injection of drug does not depend on size of administered dose.

First-order elimination

Cp

Log Cp

Time

Time

Half-life is a dependent pharmacokinetic parameter:

Half-life = 0.693 Vd Clearance Any change in the half-life of a drug can be due to a change in the clearance or volume of distribution.

t1/2 = 0.693 / ke  where ke is rate constant for drug elimination

:Clinical utility of half-life Half-life determines the time taken to reach steady-state on multiple dosing, and the time taken to eliminate most of the drug from the body when dosing is terminated. After about 5 half-lives steady-state is achieved and if dosing is terminated, most of the drug will have been eliminated from the body after 5 half-lives.

:First-order elimination of drugs Constant fraction or percent of drug is eliminated per minute.

This is shown quantitatively as: dC/dt α C where dC/dt is the rate of change of concentration C is drug concentration dC = -kE C where kE is the proportionality constant dt The negative sign denotes that the concentration is being decreased by elimination

Zero-order kinetics The rate is independent of concentration. Constant amount of drug eliminated per minute. Typical drug: ethanol

Zero-order kinetics

Cp

Time

Zero Order and First Order Kinetics Concentration of Drug in blood (μg/ml)

6 5

Zero Order

4 3 2

First Order

1 2

4

6

Time (hours)

8

10