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A review of metabolite kinetics

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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 fmi and 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 dmi converted 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.

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Abbreviations

D andMi :

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

U:

amounts in urine

D 0 and Mi0 :

represent the doses of drug andmi, respectively

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

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

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

k e andk m :

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

k m1,k m2, andk m3 :

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

k m1,1,k m1,2, andk m1,3 :

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

k mi,x :

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

k f,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

k e(mi) andk m(mi):

the rate constants for (urinary) excretion and metabolism formi

k e(m1),k e(m2), andk e(m3):

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

k m (m1),k m (m2), andk m (m3):

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

F H :

the hepatic availability of drug

F H(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,CL M,CL R, andCL H :

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

ss:

steady-state conditions

CL(mi):

the total body clearance ofmi

ss:

steadystate conditions

A e(∞):

the total amount of drug excreted unchanged into urine

A e(mi):

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

A e(mi)(∞):

the total amount ofmi excreted into urine

A mi(∞):

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

C andC(mi):

the concentrations of drug and metabolitemi in blood

ss:

steady-state conditions

AUC :

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

AUC mi :

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

f e,f x, andf m :

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

f mi :

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

g mi :

the fraction of total body clearance that formsmi

h mi :

the fraction of hepatic clearance that formsmi

d mi :

the fraction of dose of drug that formsmi

Q HV :

total hepatic blood flow

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  1. Faculty of Pharmacy, University of Toronto, M5S 1A1, Toronto, Ontario, Canada

    K. Sandy Pang

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This work was supported by the Medical Research Council of Canada, Faculty Development Award DG 262, 263, and 264.

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Pang, K.S. A review of metabolite kinetics. Journal of Pharmacokinetics and Biopharmaceutics 13, 633–662 (1985). https://doi.org/10.1007/BF01058905

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