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Journal of Pharmacokinetics and Biopharmaceutics

, Volume 13, Issue 6, pp 633–662 | Cite as

A review of metabolite kinetics

  • K. Sandy Pang
Article

Abstract

The importance of metabolites as active and toxic entities in drug therapy evokes the need for an examination of metabolite kinetics after drug administration. In the present review, emphasis is placed on single-compartmental characteristics for a drug and its primary metabolites under linear kinetic conditions. The determination of the first-order elimination rate constants for drug and metabolite are also detailed. For any ithprimary metabolite miformed solely in liver, kinetic parameters with respect to primary metabolite formation under first-order conditions require a comparison of the areas under the metabolite concentration-time curve after drug and preformed metabolite administrations. These area ratios hold regardless of the number of noneliminating compartments for the drug and metabolite. These parameters include fmiand gmi,the fractions of total body clearance that respectively furnishes mito the general circulation and forms mi,and hmi,the fraction of hepatic clearance responsible for the formation of mi.Moreover, the fraction of dose dmiconverted to form miis defined with respect to the route of drug administration. The inherent assumption of these estimates, however, requires that the extent of sequential elimination of the generated mibe identical to the extent of metabolism of preformed mi.Discrepancies have been found, and may be attributed mostly to the uneven distribution of drug-metabolizing activities as well as to the presence of diffusional barriers. Other linear systems that involve miformation from multiple organs are briefly described.

Key words

primary metabolite kinetics preformed and generated metabolites metabolite formation elimination rate constants for drug and metabolite first-order kinetics single compartment liver, kidney, and other eliminating organs 

Notation

D andMi

the amounts of drug and the ith primary metabolitemi in the body

Subscript

U

amounts in urine

D0 and Mi0

represent the doses of drug andmi, respectively

Superscripts

ia, iv, and pv; inf and pv,inf; and 1 and 2

respectively, the single intraarterial, intravenous and intraportal administrations; chronic intravenous and intraportal infusions; and injections into compartments 1 and 2

Superscripts

D,ia;D,iv;D,pv;D,inf; andD,pv,inf; andD,1 andD,2

the route of drug administration via intraarterial, intravenous, intraportal, chronic intravenous, and intraportal infusions; and input into compartments 1 and 2

Superscripts

Mi,iv;Mi,pv;Mi,inf;Mi,pv,inf; andM,2

the route ofmi administration via intravenous, intraportal, chronic intravenous infusion, and chronic intraportal infusion, and input into compartment 2

k

the overall elimination rate constant for drug

ke andkm

the (urinary) excretion rate constant and the metabolic rate constant for drug

km1,km2, andkm3

the rate constants for the formation of the first, second, and third primary metabolites (m1,m2, andm3)

km1,1,km1,2, andkm1,3

the rate constants for the formation of the first primary metabolitem1 by the biotransformation organs 1, 2, and 3

kmi,x

the general term for the rate constant for the formation of the ith primary metabolitemi by the xth organ of biotransformation

kf,mi

the apparent formation rate constant that furnishes the available metabolitemi to the systemic circulation

k(mi)

the overall elimination rate constant for the ith primary metabolitemi

ke(mi) andkm(mi)

the rate constants for (urinary) excretion and metabolism formi

ke(m1),ke(m2), andke(m3)

the (urinary) rate constants for excretion of the first, second, and third primary metabolitesm1,m2, andm3

km(m1),km(m2), andkm(m3)

the metabolic rate constants for the first, second, and third primary metabolitesm1,m2, andm3

FH

the hepatic availability of drug

FH(mi),F(m1)1,F(m1)2, F(m1)3, and F(mi)x

the hepatic availability ofmi, the availability of the first primary metabolitem 1 after the first, second, and third organs of biotransformation, and the availability of the ith primary metabolitemi after the xth organ for biotransformation

V andV(mi)

the volumes of distribution for drug andmi

CL,CLM,CLR, andCLH

total body clearance and metabolic, renal, and hepatic clearances for drug

Subscript

ss

steady-state conditions

CL(mi)

the total body clearance ofmi

Subscript

ss

steadystate conditions

Ae(∞)

the total amount of drug excreted unchanged into urine

Superscripts

Ae(mi)

the cumulative amount ofmi excreted into urine up to the timet designated

Superscripts

Ae(mi)(∞)

the total amount ofmi excreted into urine

superscripts

Ami(∞)

the total amount ofmi in the body formed from the administration of drug

superscripts

C andC(mi)

the concentrations of drug and metabolitemi in blood

Subscript

ss

steady-state conditions

superscripts

AUC

the area under the blood concentration-time curve for drug from time equals zero to infinity

superscripts

AUCmi

the area under the curve ofmi from time equals zero to infinity

superscripts

fe,fx, andfm

the fraction of total body clearance of an i.v. dose of drug that is excreted unchanged, removed by other mechanisms, and metabolized

fmi

the fraction of total body clearance that furnishes the available metabolitemi to the systemic circulation

gmi

the fraction of total body clearance that formsmi

hmi

the fraction of hepatic clearance that formsmi

dmi

the fraction of dose of drug that formsmi

superscripts

QHV

total hepatic blood flow

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Copyright information

© Plenum Publishing Corporation 1985

Authors and Affiliations

  • K. Sandy Pang
    • 1
  1. 1.Faculty of PharmacyUniversity of TorontoTorontoCanada

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