The role of metabolites in predicting drug-drug interactions: focus on irreversible cytochrome P450 inhibition

Abstract

The irreversible inhibition of cytochrome P450 (CYP) enzymes can cause significant drug-drug interactions (DDIs). The formation of metabolites is fundamental for the inactivation of CYP enzymes. Of the 19 CYP enzyme inactivators for which the mechanism of action has been established, 10 have circulating metabolites, which are on the metabolic pathway to inactivation of the CYP enzyme. Because inactivation of CYP enzymes usually requires multiple metabolic steps, the prediction of interactions between metabolites and CYPs in vivo may require complex models and the availability of data generated in vitro from each metabolite. Data discussed in this review suggest that circulating metabolites are more important in CYP inhibition in vivo than has been acknowledged.

Figure 1

Pathways to irreversible inhibition of P450 enzymes. Pathways a and b indicate the two metabolic routes to inactivate P450 (red boxes) by MI complex formation (green boxes) or by protein alkylation (blue boxes). The off path metabolites (purple box) are not directly involved in the inactivation of the P450 enzymes. Circulating metabolites (pathway a and b) are able to rebind to the P450 enzymes and are further metabolized to inactivate the P450 enzymes. The deactivated metabolites (pathway b) are dead end products and often detected in vitro.

Figure 2

Proposed route of alkyl amine metabolism to MI complex. Solid arrows indicate P450 metabolic reactions indentified in HLMs, dashed arrows are proposed metabolic reactions on route to MI complex formation but have not been verified. Blue compounds are known circulating metabolites, green compounds have been shown to form MI complexes but are not known circulating metabolites, the black colored compound is the proposed proximal species to MI complex formation, the red colored compound is the inactivated P450 enzyme. The pathways were adapted from references [21, 22, 24]

Figure 3

Structures of anti-HIV protease inhibitors that irreversibly inhibit CYP3A4 via an MI complex formation. The arrows indicate sites of metabolism for known circulating metabolites (Table 2).

Figure 4

Structures of three drugs that form protein adducts with P450 enzymes. Circles indicate the site of metabolism that leads to inactivation, the arrows indicate site of metabolism for off path circulating metabolites (Table 1). *indicates the site of glucuronidation to form the inactivating glucoronide metabolite.

Figure 5

Structures of three drugs that result in MI complex formation with P450 enzymes. Circles indicate the site of metabolism that leads to inactivation, the arrows indicate site of metabolism for off path circulating metabolites (Table 2).