Drug Metabolism in Drug Design and Development Basic Concepts and Practice

Ki. If the inhibition process is strictly noncompetitive, the IC 50 should be equal
to theKi. For competitive inhibition, IC 50 values are substrate concentration
dependent, and the IC 50 determined at low substrate concentrations will be
very close toKisince IC 50 = (1 + [S]/Km) Ki. The predicted magnitude of the
interaction between ritonavir and saquinavir based on the IC 50 values obtained
with various substrates is shown in Figure 7.2. Thein vivostudy has shown that
ritonavir increased saquinavir AUC by 48-fold. The prediction using total
ritonavir peak concentrations as [I] and IC 50 values from different substrates is
closer to the actual ratio compared to the ratio that is obtained with when
unbound fraction is used as [I].

7.4.1.4 CYP2C8 CYP2C8 has emerged recently as a key enzyme for
clearance of several drugs, especially oral antidiabetic drugs (Totah and
Rettie, 2005). Therefore, CYP2C8 is now recommended forin vitroandin vivo
drug interaction studies by the FDA (FDA, 2006). Based on current
knowledge, gemfibrozil is considered to be a strong, specific CYP2C8 inhibitor
(Ogilvie et al., 2006). Gemfibrozil increases the plasma concentrations of
rosiglitazonein vivo(Niemi et al., 2003a). Moreover, cerivastatin metabolism is
believed to be partially inhibited by gemfibrozil via a CYP2C8 pathway.
Inhibition of this pathway is possibly contributed to serious adverse events
including rhabdomyolysis (Shitara et al., 2004).
The study of gemfibrozil, itraconazole, and their combination on the
pharmacokinetics of repaglinide has further confirmed that gemfibrozil is a
strong inhibitor of CYP2C8 (Fig. 7.3). When both the CYP2C8 (major)- and
CYP3A4 (minor)- mediated metabolic pathways of repaglinide are blocked,
the synergistic accumulation of repaglinide exposure is observed (Table 7.6)
(Niemi et al., 2003b). Repaglinide is now recommended as a sensitive CYP2C8
substrate for humanin vivodrug interaction studies.

AUC fold increase

0

1

2

3

4

5

6

7

8

9

Ro

sigli

taz

on

e

Ce

riv a

stati

n

Repaglinide

FIGURE 7.3 Gemfibrozil 600 mg for 3 days increased the exposures of CYP2C8
substrate drugs (Backman et al., 2002; Niemi et al., 2003).

DRUG–DRUG INTERACTION STUDIES 223