Fundamentals of Medicinal Chemistry

the drug. The rate of change of concentration of a metabolite (dM/dt) in the

plasma is given by:

dM=dt¼rate of formationrate of elimination (9:1)

Since most biological processes exhibit first order kinetics Equation (9.1)

becomes:

dM=dt¼kfAkmAm (9:2)

wherekfandkmare the rate constants for the metabolite’s formation and elimin-

ation processes respectively. Ifkf>kmthere will be an accumulation of the

metabolite in the patient. However, it is not easy to determinekf. Therefore, as

all the processes involvedin drug elimination are normally first order, thekoverall

rate constant for all the processes is used becausek¼kfþk 0 and it is relatively

easy to determine. Consequently, ifk>kmthe metabolite will belikelyto accumu-

late in the plasma as it is formed faster than it is eliminated. However, ifk<kmthe

metabolite isunlikelyto accumulate in the body as the metabolite is eliminated

faster than it is formed. The values ofkandkmcan be determined experimentally

from log plots of plasma measurements of the drug and metabolite (Figure 9.3).

(a)

Time

Slope = k

Drug

logC logC

Time

Slope = k

Slope = km

Metabolite

Drug

Metabolite

Slope = km

(b)

Figure 9.3 Representations of typical log concentration–time plots for a drug and metabolite

exhibiting first order kinetics showing the general changes when (a)k>kmand (b)k<km

9.7 Drug metabolism and drug design

A knowledge of the metabolic pathway of a drug may be used to design

analogues that have a different metabolism to that of the lead. This change of

DRUG METABOLISM AND DRUG DESIGN 193