Drug Metabolism in Drug Design and Development Basic Concepts and Practice

clinical observed DDIs.

AUC½IŠ

AUCctr

¼ 1 þ

kinactfu½IŠ

ðKIþfu½IŠÞkE

ð 16 : 11 Þ

If the CYP in gut contributes to the metabolism of a drug and is inhibited by
a mechanism-based inhibitor, a change of bioavailability of the drug in gut
should be taken into account. The ratio ofFg,[I]toFg,ctr(the intestinal wall
availability in the presence and absence of inhibitor) can be incorporated into
the model (Equation 16.12). The ratio ofFg,[I]toFg,ctris estimated from the
relative change in CLint,g (gut intrinsic clearance) caused by the inhibitor
(Equation 16.13).

AUC½IŠ

AUCctr

¼

Fg;½IŠ

Fg;ctr

1

fm

1 þ

kinactfu½IŠ

ðKIþfu½IŠÞkE

0

B

B@

1

C

CAþð 1 fmÞ

ð 16 : 12 Þ

Fg;½IŠ

Fg;ctr

¼

1

Fg;ctrþð 1 Fg;ctrÞ

CLint;g;½IŠ

CLint;g

 ð 16 : 13 Þ

16.5.3 Factors Affecting the Prediction of Drug–Drug Interactions

Although research on the prediction of DDI fromin vitrodata achieved some
extent in success, many unresolved issues that affect accurate prediction need to
be addressed and can complicate the prediction. These factors include (1) choice
of steady state plasma concentration ([I]max, [I]aveor [I]trough), or concentration in
total hepatic circulation ([I]hept,inlet) that approaches that at active site of enzyme
(hepatic intracellular concentration); (2) impact of unbound fraction of the drug
(fu) in plasma and liver microsomes (Austin et al., 2002; Giuliano et al., 2005),
particularly for highly bound inhibitors; (3) accuratein vitroassessment onfmof
individual victim drugs (interacting drugs) for the inhibited enzyme. If a drug is
metabolized by multiple enzymes that are inhibited by the inhibitor,fmvalue of
the drug is contributed by multiple enzymes (fm=fm, CYP3A4+fm, CYP2C8...)
(Rodrigues, 2005); (4) the enzyme inhibition by metabolite(s) formed; (5) enzyme
inhibition occurring in intestine (CLint,g), which may underestimate the
prediction; (6) concurrence in both reversible and mechanism-based inhibition;
(6) concurrence in induction and inhibition of the enzyme by the inhibitor
(Greenblatt et al., 1999); (7) effect of transporters or poor permeability on
intracellular concentration of the inhibitor (Zhang et al., 2006); (8) effect of non-
CYP enzymes (i.e., elimination of parent substrates by conjugation pathways) on
fm; (9) choice ofKEvalue for MBI. Varying half-lives for CYP3A4 recovery have
been reported in literature (t1/2= 9–144 h, KE= 0.693/t1/2) (Correia, 1991;
Fromm et al., 1996; Greenblatt et al., 2003; Hsu et al., 1997; Lai et al., 1978;

PREDICTION OF HUMAN DRUG–DRUG INTERACTIONS 537