Drug Metabolism in Drug Design and Development Basic Concepts and Practice

is important when making projections to keep in mind the overall contribution of
an enzyme. For example, expressed P450 enzyme and microsomal chemical
inhibition studies may indicate that CYP3A4 is the only P450 involved in the
metabolism of a compound. However, if the compound is estimated to be 50%
cleared by renal excretion and 20% of the fraction metabolized is projected to be
via N-acetylation, then the overall fraction metabolized via CYP3A4 would be
projected to be no greater than 40% (i.e.,fm(CYP3A4)0.5 0.8 1).
The estimatedfm(enz)value is utilized in the estimation of the drug–drug
interaction potential of the compound of interest (Eq. 15.1) (Ito et al., 2005;
Rowland and Matin, 1973). For Equation 15.1, the ratio of the systemic
exposures of the inhibited compound in its inhibited versus noninhibited state
(AUCi/AUC) is a function of thein vivoinhibitor concentration [I], the binding
affinity of the inhibitor for the inhibited enzyme (Ki), and the fraction of the
drug of interest that is metabolized by the inhibited pathway (fm(enz)). For
orally administered drugs where the inhibitor also impacts intestinal
metabolism, the effect of the inhibitor on the ratio of the systemic exposures
of the inhibited compound is more complicated (see Chapter 5). However,
fm(enz)for a particular drug by the inhibited metabolic pathway is also a key
parameter for this projection as well. Essentially, the more the drug of interest
is eliminated by the inhibited metabolic pathway the larger the potential drug–
drug interaction (for a given [I] andKi) (Fig. 15.8).

AUCi

AUC

¼

1

fmðenzÞ

1 þ½KIŠi

þð 1 fmðenzÞÞ

ð 15 : 1 Þ

FIGURE 15.8 Simulation of changes in the AUCi/AUC ratio of a drug as a function
offm(enz)using Equation 15.1.

RADIOLABELED REACTION PHENOTYPING 503