THE EMERGING ROLE OF CYTOCHROME-P450 3A IN PSYCHOPHARMACOLOGY

Recent advances in molecular pharmacology, have allowed the characteri zation of the specific isoforms that mediate the metabolism of various medications. This information can be integrated with older clinical o bservations to begin to develop specific mechanistic and predictive mo dels of psychotropic drug interactions. The polymorphic cytochrome P45 0 2D6 has gained much attention, because competition for this isoform is responsible for serotonin reuptake inhibitor-induced increases in t ricyclic antidepressant concentrations in plasma. However, the cytochr ome P450 3A subfamily and the 3A3 and 3A4 isoforms (CYP3A3/4) in parti cular are becoming increasingly important in psychopharmacology as a r esult of their central involvement in the metabolism of a wide range o f steroids and medications, including antidepressants, benzodiazepines , calcium channel blockers, and carbamazepine. The inhibition of CYP3A 3/4 by medications such as certain newer antidepressants, calcium chan nel blockers, and antibiotics can increase the concentrations of CYP3A 3/4 substrates, yielding toxicity. The induction of CYP3A3/4 by medica tions such as carbamazepine can decrease the concentrations of CYP3A3/ 4 substrates, yielding inefficiency. Thus, knowledge of the substrates , inhibitors, and inducers of CYP3A3/4 and other cytochrome P450 isofo rms may help clinicians to anticipate and avoid pharmacokinetic drug i nteractions and improve rational prescribing practices.