Drug Metabolism in Drug Design and Development Basic Concepts and Practice

16.5 PREDICTION OF HUMAN DRUG–DRUG INTERACTIONS FROM

IN VITROCYP INHIBITION DATA

When an enzyme inhibitor is identified to change biotransformation profiles of
a victim drug or drug candidate, drug–drug interactions probably occur,
largely due to the change in enzyme activity. It may lead to severe clinically
adverse effects associated with metabolism-based DDIs. Thus, evaluation of
the compounds as inhibitors of the DMEs and prediction of the probablein
vivoDDI potentials are crucial at the discovery stage.In vitrokinetic data from
enzyme inhibition are typically required to assess the degree of the inhibition
(IC 50 andKifor reversible enzyme inhibition andKIandkinactfor mechanism-
based inhibition). Apparent intrinsic clearance (CLint,[I]) in the presence of
inhibitor can be calculated. Ratios of systemic exposure in the presence and
absence of inhibitor can be determined according to appropriate in vitro
approaches (Azie et al., 1998; Bjornsson et al., 2003; Ito et al., 1998a, 1998b,
2004; Kanamitsu et al., 2000; Lin and Lu, 2001; Mayhew et al., 2000; Obach,
2003; Obach et al., 2005, 2006; Shou, 2005; Thummel and Wilkinson, 1998;
Wang et al., 2000, 2004).

16.5.1 Reversible CYP Inhibition

Since enzyme inhibition involves reversible mechanisms,CLint,[I]may vary with
regard to the type and concentration of inhibitor. The concentrations of an
inhibitor (or drug) that are relevant to clinical application can be approached
for the prediction in thein vivosituation. In practice, a ratio in AUC, hepatic
clearance (CLhept), plasma concentration at steady state (Css), or intrinsic
clearance (CLint) caused by metabolism-based DDIs is commonly used to
assess the degree of metabolism inhibitionin vivo (Eq. 16.7). If a drug is
eliminated due to both metabolism and renal excretion, the fraction of the drug
metabolized by the inhibited enzyme (fm) should be introduced to the
prediction. With inclusion offm, the ratio change in AUC in the presence
and absence of an inhibitor can be expressed for competitive and
noncompetitive (Eq. 16.8).

AUC½IŠ

AUCctr

¼

Css;½IŠ

Css

¼

CLhept

CLhept;½IŠ

¼

CLint

CLint;½IŠ

ð 16 : 7 Þ

AUC½IŠ

AUCctr

¼

1

fm

1 þ

fu½IŠ

Ki

þð 1 fmÞ

ð 16 : 8 Þ

wherefmrepresents the fraction of CYP-dependent metabolism catalyzed by
the inhibited CYP; Ki the inhibitor dissociation constant;futhe unbound
fraction of inhibitor in plasma and [I] the projected plasma concentration of

534 ANALYSIS OFIN VITROCYTOCHROME P450 INHIBITION