INHIBITION AND INDUCTION OF CYTOCHROME-P450 AND THE CLINICAL IMPLICATIONS

The cytochrome P450s (CYPs) constitute a superfamily of isoforms that play an important role in the oxidative metabolism of drugs. Each CYP isoform possesses a characteristic broad spectrum of catalytic activit ies of substrates. Whenever 2 or more drugs are administered concurren tly, the possibility of drug interactions exists. The ability of a sin gle CYP to metabolise multiple substrates is responsible for a large n umber of documented drug interactions associated with CYP inhibition. In addition, drug interactions can also occur as a result of the induc tion of several human CYPs following long term drug treatment. The mec hanisms of CYP inhibition can be divided into 3 categories: (a) revers ible inhibition; (b) quasi-irreversible inhibition:, an (c) irreversib le inhibition. In mechanistic terms, reversible interactions arise as a result of competition at the CYP active site and probably involve on ly the first step of the CYP catalytic cycle. On the other hand, drugs that act during and subsequent to the oxygen transfer step are genera lly irreversible or quasi-irreversible inhibitors. Irreversible and qu asi-irreversible inhibition require at least one cycle of the CYP cata lytic process. Because human liver samples and recombinant human CYPs are now readily available, in vitro systems have been used as screenin g tools to predict the potential for in vivo drug interaction. Althoug h it is easy to determine in vitro metabolic drug interactions, the pr oper interpretation and extrapolation of in vitro interaction data to in vivo situations require a good understanding of pharmacokinetic pri nciples. From the viewpoint of drug therapy, to avoid potential drug-d rug interactions, it is desirable to develop a new drug candidate that is not a potent CYP inhibitor or inducer and the metabolism of which is not readily inhibited by other drugs. In reality, drug interaction by mutual inhibition between drugs is almost inevitable, because CYP-m ediated metabolism represents a major route of elimination of many dru gs, which can compete for the same CYP enzyme. The clinical significan ce of a metabolic drug interaction depends on the magnitude of the cha nge in the concentration of active species (parent drug and/or active metabolites) at the site of pharmacological action and the therapeutic index of the the drug. The smaller the difference between toxic and e ffective concentration, the greater the likelihood that a drug interac tion will have serious clinical consequences. Thus, careful evaluation of potential drug interactions of a new drug candidate during the ear ly stage of drug development is essential.