The total body clearance is the volume of the plasma or blood which is completely cleared from the drug per unit time. It has units of volume/time.

The CL_T for a drug is constant within a patient (dose and concentration independent) when the elimination processes follow first-order kinetics.

The total body clearance is a measure of the efficiency of all eliminating organs in eliminating the drug and it is the sum of all organ clearances (i.e. CL_T is the sum of the renal clearance, hepatic clearance and all other organ clearances).

The elimination rate constant and the half life (the dependent pharmacokinetic parameters) are dependent on (is determined from) the total body clearance and the volume of distribution (the independent pharmacokinetic parameters).

CLT

Vd = k and

CLT

Vd =

0.693

t 1/2

The metabolite total body clearance is the volume of the plasma or blood which is completely cleared from the metabolite per unit time. It has units of vloume/time.

The CL_T(m) for the metabolite is constant within a patient (dose and concentration independent) when its elimination processes follow first-order kinetics.

The CL_T(m) is a measure of the efficiency of all eliminating organs in eliminating the metabolite.

The metabolite elimination rate constant and the metabolite half life (the dependent pharmacokinetic parameters) are dependent on (is determined from) the metabolite total body clearance and the metabolite volume of distribution (the independent pharmacokinetic parameters).

CLT(m)

Vd_(m) = k_(m) and

CLT(m)

Vd_(m) =

0.693

t 1/2(m)

The amount of the metabolite formed after drug administration depends on the dose of the drug and f_m. If f_m is equal to unity (1) for a particular metabolite, this means that the entire dose of the parent drug is converted to that metabolite.

Drugs that undergo parallel metabolism to more than one metabolite have different f_m values for each metabolite. The sum of these f_m values should not be more than one, but it does not have to be equal to one (when the drug elimination involves a pathway other than metabolism).

This fraction should be dose independent when drug elimination follows first-order kinetics. Also, this fraction should not be different for a particular drug in a particular patient after different routes of administrations, if the metabolite is not formed during drug absorption after extravascular administration.

The formation clearance of the metabolite is the fraction of the drug CL_T that is responsible for the formation of the metabolite. It is the product of the drug CL_T and the fraction of the drug dose converted to the metabolite (f_m).

When all the administered drug dose is metabolized to one metabolite, the formation clearance should be equal to the CL_T of the drug (f_m = 1).

When multiple metabolites are formed by parallel metabolism, each metabolite will have its own formation clearance. The sum of the formation clearances for all metabolites should not be more than the drug CL_T. However, the sum of the formation clearances of the metabolites will not be equal to the drug CL_T if the drug elimination involves pathways other than drug metabolism.