Drug Metabolism in Drug Design and Development Basic Concepts and Practice

versus fraction metabolized in relation to the ratio of [I]/Ki. The lines labeled 1,
2, and 3 represent increasing ratios (i.e., increasing drug interaction potential).
At a given [I]/Kiratio, the change in AUC is significant (>2-fold) only when the
inhibited CYP contributes to greater than 60% of total clearance
(fm fm,P450>0.6). If additional pathways are involved in clearance

FIGURE 5.2 Representative plot of how AUC changes in regard tofm fm,P450and
[I]/Ki.Ki, dissociation constant of inhibitor-enzyme complex; [I], inhibitor concentration
at the enzyme;fm, fraction of dose metabolized via all CYPs;fm,P450, fraction of total
CYP-mediated metabolism catalyzed by inhibited CYP form; the product offm fm,P450
represents the contribution of a specific CYP enzyme to overall clearance.

TABLE 5.3 Considerations and assumptions for predictingin vivodrug–drug
interactions via inhibition.

Choice of [I] Key considerations References

Static [I] Different [I]: steady-state
plasmaCmax;Cmax,fu;
portal veinImax;orImax,fu

Chien (2003),

Ito et al. (2004),

Ito et al. (2002),

Ito (1998b),

Obach et al. (2006)

Parallel pathways of drug

elimination

Ito et al. (2005),

Obach (2006)

Time-dependent CYP

inhibition

Galetin et al. (2006),
Obach (2006)
Inhibitor absorption rate Brown et al. (2005),
Obach (2006)
Intestinal inhibition Galetin (2006),
Obach (2006)
Dynamic [I] PBPK, simulated [I] Chien (2003),
Kanamitsu (2000)

Abbreviations: [I], inhibitor concentration; Cmax, maximum plasma concentration; Cmax,fu,
maximum free plasma concentration;Imax, maximum portal vein concentration;Imax,fu, maximum
free portal vein concentration; PBPK, physiologically-based pharmacokinetics.

118 METABOLISM-MEDIATED DRUG–DRUG INTERACTIONS