Potential strategies for minimizing mechanism-based inhibition of cytochrome P450 3A4

Cytochrome P450 (CYP) 3A4, one of the most abundant hepatic Phase I enzymes, is able to metabolize more than 50% currently available therapeutic drugs. However, this enzyme is subject to mechanism-based inhibition by a number of xenobiotics and commonly-used drugs, which is characterized by NADPH-, time- and concentration-dependent enzyme inactivation, occurring when the parental drugs are converted by CYPs to reactive metabolites. The inactivation of CYP3A4 by drugs may lead to important clinical consequences, because the inhibition frequently causes unfavorable drug-drug interactions and toxicity, depending on many factors associated with the enzyme, drugs and the patients. Some drugs (e.g. mibefradil) have been withdrawn from the market since they are eventually identified as CYP3A4 inactivators that can cause toxicity-related fatal events. Clinical professionals should take proper approaches to avoid such toxicities when using drugs that are mechanism-based CYP3A4 inhibitors, in particular, when in combination with other drugs that are substrates for CYP3A4. These include early identification of drugs behaving as CYP3A4 inactivators, rational use of such drugs (e.g. safe drug combination regimen, dose adjustment or discontinuation of therapy when toxic drug interactions occur), close therapeutic drug monitoring, and prediction of the risks for potential drug-drug interactions. Clinicians should have sound knowledge on drugs that behave as CYP3A4 inactivators and take cautions for their clinical use. A fifth approach is the design of drugs with minimal potential for behaving as a CYP3A4 inactivator. These new drugs are so called "hard drugs" which are non-metabolizable (thus mechanism-based CYP3A4 inhibition is avoided), and excreted through either the bile or kidney, with predictable pharmacokinetics. Further studies are needed to explore the suitable approaches for minimizing mechanism-based inhibition of CYP3A4 and thus avoiding potential toxicities and unfavorable drug-drug interactions.