Mechanisms and significance of inhibitory drug interactions involving cytochrome P450 enzymes (review).

The cytochrome P450 (CYP) superfamily of enzymes are catalytically competent toward an unusually diverse array of lipophilic chemicals. The major microsomal CYP in human liver, CYP3A4, participates in the oxidative biotransformation of most drugs. Accordingly, it is not surprising that CYP activity is also readily inhibited by many drugs. Such interactions may elicit adverse toxic effects in patients and this situation is exacerbated by the practise of polypharmacy. Clinical studies have suggested that the judicious selection of drugs for combination therapy may be a relatively simple means by which drug interactions can be avoided. Such studies will rely heavily on basic information obtained from biochemical studies that describe the substrate preferences of CYPs and molecular studies on the factors that determine CYP levels in subjects. This review focuses on the information that is emerging on CYP substrate and inhibitor specificity, protein structure from homology modelling approaches and CYP expression in liver as it emerges from molecular analyses. With information of this type, drawn from several different sources, it will eventually be possible to reconcile the likelihood of drug interactions produced by specific combinations of drugs and predict those individuals who are at risk from such interactions, as a consequence of their genetic makeup.