CYP3A4 and MDR Mediated Interactions in Drug Therapy

Multiple drug therapy is recommended in many disease states including AIDS, cancer, diabetes, and stroke. Therefore, drug-drug interactions can result in changes in pharmacological or toxicological response following concomitant administration of many therapeutic agents. It has become evident that two factors i.e. drug efflux pump- P-glycoprotein (MDR gene product) and metabolizing enzyme- CYP3A4 play major roles in this process. These two key proteins regulate all pharmacokinetic and pharmacodynamic interactions through the process of drug absorption, metabolism, disposition and elimination. Co-administration of two or more drugs can affect these processes due to altered functions of P-glycoprotein (P-gp) and CYP3A4 and consequently change clinical response and final outcome. After co-administration, some drugs may induce the activity of P-gp and/or CYP3A4 resulting in subtherapeutic blood levels and therapeutic failure due to reduced absorption and/or increased metabolism. Conversely, inhibition(s) of P-gp and/or CYP3A4 can cause enhanced plasma concentration and therefore, drug toxicity. Overlapping substrate specificities to these proteins make it difficult to understand perplexing pharmacokinetic interactions with multidrug regimens. Inter-patient variability of drug response can occur due to change in genetic profiles, intake of food, herbal supplement, and recreational drugs. In this review, we have outlined several clinically important CYP and MDR-mediated drug-drug interactions of antiretroviral agents, antineoplastic agents, azole antifungals, statins, methadone, antibacterials, cardiovascular medicines, immune modulators, recreational drugs and herbal agents. Mechanisms by which such drug interactions occur have been briefly discussed in some of the examples.