Drug Metabolism in Drug Design and Development Basic Concepts and Practice

5.4 Reaction Phenotyping

For any established drug or a NCE, it is important to understand the routes of
elimination, the contribution of each route to overall clearance and the
enzyme(s) involved in metabolism. A human radiolabeled study provides
critical information related to the fraction of the dose cleared via CYP-
dependent metabolism (fm).In vitroreaction phenotype data are also important
(Rodrigues, 1999). In this instance, one uses different approaches to determine
the contribution or each CYP form toward total CYP-mediated metabolism
(fm,P450). The two data sets are then integrated because the product offm
andfm,P450(i.e.,fm fm,P450) is one of the key factors that determines the
magnitude of a DDI (Table 5.2). As shown in Table 5.7, drugs largely
metabolized by a single CYP enzyme are far more susceptible to drug–
drug interactions. Itraconazole is a CYP3A4 inhibitor and gemfibrozil-O-
glucuronide (major circulating metabolite of gemfibrozil) is a mechanism-based
inhibitor of CYP2C8 (Niemi et al., 2003, 2005; Ogilvie et al., 2006). This
particular combination would significantly impact metabolic clearance
mediated by both CYP3A4 and CYP2C8. As a result, a significant
drug–drug interaction is observed for repaglinide, a CYP3A4 and CYP2C8
substrate (fm fm,P450approaching 1.0). In comparison, the two enzymes play
minor roles in the overall clearance of netaglinide and the magnitude of the
DDI is reduced.
Likewise, marked variability in pharmacokinetics can be anticipated for drugs
that are primarily metabolized by polymorphic CYP enzymes such as CYP2D6,
CYP2C9 and CYP2C19 (Ma et al., 2004; Nagata and Yamazoe, 2002). For
example, the incidence of CYP2C19 poor metabolizers (PMs) is as high as 38%
in Asians (e.g., Japanese and Chinese) and less than 15% in Caucasians
(Rodrigues and Rushmore, 2002). Aside from pharmacokinetic variability
associated with CYP2C19 PM subjects, inhibition of alternative clearance

TABLE 5.7 Effect of gemfibrozil and itraconazole on the pharmacokinetics
of two insulin secretogogues.a

Netaglinide Repaglinide

fm 0.80 0.97
fm,P450 fm fm,P450 fm,P450 fm fm,P450
fm,CYP2C9 0.70 0.56
fm,CYP3A4 0.30 0.24 0.53–1.0 0.51–0.97
fm,CYP2C8 0.47 0.45
Effect of gemfibrozil + itraconazole
on AUC (fold-increase)

1.5  20

Abbreviations:fm, fraction of the dose metabolized by all CYPs;fm,P450, fraction of total CYP-
dependent metabolism catalyzed by each CYP;fm fm,P450, contribution of a specific CYP enzyme
to overall clearance.
aBidstrup et al. (2003), Niemi et al. (2003), Niemi et al. (2005).

126 METABOLISM-MEDIATED DRUG–DRUG INTERACTIONS