SIGNIFICANCE OF VOLUME OF DISTRIBUTION

Eqn.

Drug is concentrated in extravascular compartment e.g. drug is bound to peripheral tissues

® C_O becomes small

® V_d becomes large

Drug is concentrated in blood compartment e.g. drug is highly bound to plasma protein

® C_O becomes large

® V_d becomes small

Expression of V_d.

V_d is a volume term that can be expressed as a simple volume

or in terms of percent of body weight.

Assumption

A 1 litre body volume is equal to 1 kg body weight.

e.g. V_d, = 3500 mL for a subject

Body weight of the subject = 70 kg, then

V_d expressed as % body weight =

V_d > 100% Þ that the drug is concentrated in certain tissue compartments

For each drug the V_d is constant. In certain physiologic state, the apparent V_d for the drug may be altered

e.g. in oedematous conditions, the total body water and total extracellular water increase

® large V_d.

e.g. lean body mass in old age ® small V_d.

CLEARANCE

Definition: Clearance is defined as the volume of plasma fluid that is cleared of drug per unit time.

Mass approach

Drug elimination expressed in

Units:

Advantage:

1) Simple, absolute, and unambiguous.

2) For a zero order elimination process,

k_O does not change with time

So in case of zero order elimination rate process CLEARANCE can be expressed as

Disadvantage:

1. For a first-order elimination, drug clearance expressed as mass per unit time is not constant.

Volume approach

Drug Elimination expressed as

Unit:

Advantage:

For a first-order elimination, drug clearance expressed as volume per unit time is constant.

In case of a first order elimination rate

Therefore

The negative sign refers to the drug exiting from the body.

N.B. The drug concentration in the body will gradually decline such that the mass of drug removed over time is not constant. The plasma volume in the healthy state is relatively constant because water lost through the kidney is rapidly replaced with fluid absorbed from the gastrointestinal tract.

Clearance from drug eliminating tissues:

Elimination of drug from the body involves

(a) excretion through kidney,

(b) metabolism in the liver,

(d) excretion through other eliminating organs.

Clearance at an individual organ level is called as organ clearance. It can be estimated by dividing the rate of elimination by each organ with the concentration of drug present in it. Thus,

Other organ clearance,

The total body clearance (CL_T) also called as total systemic clearance, is the sum of all the organ clearances, provided all the elimination processes are following first order rate process.

Hence,

Total Systemic Clearance, CL_T = CL_R + CL_H + CL_Others

Non-renal Clearance: clearance by all organs other than kidney is called non-renal clearance CL_NR .

CL_NR = CL_T - CL_R

Following equations can be written for total, renal and hepatic clearances:

CL_T = k_EV_d k_E = overall elimination rate constant

CL_R = k_e V_d k_e = elimination rate constant through renal route

CL_H = k_m V_d k_m = elimination rate constant by metabolism in the liver

Since k_E = 0.693 / t_1/2 where t_1/2 = elimination half-life of the unchanged drug

From the equation CL_T = k_E V_d

CL_T = 0.693 V_d / t_1/2

0.693 V_d

For renal clearance: CL_R =

t_1/2 of urinary excretion

0.693 V_d

For hepatic clearance: CL_H =

t_1/2 of hepatic clearance by metabolism

Determination of clearance values:

· For drugs given as i.v. bolus:

CL_T = X₀/AUC (ml/min)

· For drugs administered extravascularly (e.g. orally)

CL_T = FX₀/AUC (ml/min)

where F = fraction of dose available in the systemic circulation.

· For a drug given i.v. bolus, the renal clearance (CL_R) may be estimated by determining the total amount of unchanged drug excreted in urine, X_U and AUC at infinite time.

DOWN LOAD--------ORIGINAL--------SIGNIFICANCE

FOR PHARMACEUTICS THEORY