Drug Metabolism in Drug Design and Development Basic Concepts and Practice

degrees of success (Table 5.2). General assumptions underpinning in vivo
predictions usingin vitrodata include (1) liver is the organ for drug clearance;
(2) a well-stirred model of hepatic clearance; and (3)in vivoconditions are
similar to thosein vitro(Ito et al., 1998a). A simple and well-accepted rule is the
[I]/Kiratio (Bjornsson et al., 2003), where [I] is the inhibitor concentration at
the CYP enzyme andKiis the inhibition constant that can be experimentally
determinedin vitro. A ratio of [I]/Ki>1 suggests an interaction is highly likely,
whereas ratios of 0.1<[I]/Ki<1 or [I]/Ki<0.1 indicate that an interaction is
likely or not likely, respectively. Although the quality ofin vitroCYP inhibition
data is a determining factor for accurate predictions (Wienkers and Heath,
2005), inhibitor concentrations at the enzyme site and the interplay of different
clearance pathwaysin vivoare two of the most important unknowns that often
derail successful predictions. Because the actual [I] cannot be measured,
various correction factors and assumptions have been considered and specific
examples are summarized in Table 5.3. Moreover, dynamic [I] as opposed to
static [I] has also been examined using physiologically-based pharmacokinetic
models (Chien et al., 2003; Kanamitsu et al., 2000). In addition, other factors,
such as time-dependent inhibition, involvement of intestinal CYP enzymes, and
other clearance pathways should also be considered. For example, Fig. 5.2
describes the change in area under the plasma concentration curve (AUC)

TABLE 5.2 Pharmacokinetic model describing aninhibitory drug–druginteraction.a

General equation

AUCðiÞ

AUC¼

1

fm fm;P450

CLint=CLint;i



þ 1 ðfm fm;P450Þ

CLint

CLint;i

¼

Reversible competitive
and non-competitive inhibition

1 þ

½IŠ

Ki

Reversible uncompetitive inhibition 1 þ
½IŠ
Ki



½SŠ

½SŠþKm



Mechanism-based inhibition Kdegþ

½IŠkinact

½IŠþKI

Kdeg

Abbreviations: AUCi, area under the curve in the presence of an inhibitor; AUC, area under the
curve in the absence of an inhibitor; CLint,i, intrinsic clearance in the presence of an inhibitor; CLint,
intrinsic clearance in the absence of an inhibitor;fm, fraction of dose metabolized via CYPs;fm,P450,
fraction of total CYP-mediated metabolism catalyzed by inhibited CYP form; [I], inhibitor
concentration; [S], substrate concentration; Ki, dissociation constant of inhibitor–enzyme complex;
Km, dissociation constant of substrate–enzyme complex;kinact, rate constant of CYP inactivation;
Kdeg, rate constant of CYP degradation or turnover;KI, half maximal rate of inactivation (exact
physical meaning is not defined).
aIto et al. (1998b).

ENZYME INHIBITION 117