Cytochrome P450 enzymes: interpretation of their interactions with selective serotonin reuptake inhibitors. Part II.

The SSRIs have been used as an example to show how one might interpret the available evidence to draw conclusions about the relationships between drugs and P450s. Under what circumstances might one apply the knowledge of such relationships? First, the clinical implications must be considered when drugs with a narrow therapeutic index are coprescribed with other drugs that may affect P450s. For example, good clinical practice demands that before a TCA is coprescribed with another drug, the physician be aware of the potential for the second drug to interact with CYP2D6. Second, it may be helpful to consider P450 enzymes when adverse events occur during polypharmacy. It may happen that a known side effect of one drug occurs. Rather than attributing this to patient sensitivity, the physician should consider the possibility that a pharmacokinetic drug interaction increased plasma drug concentration, which in turn enhanced the probability of such an occurrence. Even when a pharmacokinetic drug interaction is considered as a possible cause, an appreciation of the role of P450s may lead to the realization that an interaction was not only possible but that it was likely. Finally, copharmacy can be used intentionally to produce controlled interactions. Indeed, planned pharmacokinetic drug interactions at the level of P450s have been proposed to reduce cyclosporine dosage requirements, to reduce variability of TCA levels, and to manipulate the contribution of alternative metabolic pathways to minimize toxic effects. As long as pharmaceuticals are metabolized by the P450 system, interactions with the various isozymes will be inescapable. It is fortunate that understanding them is becoming more tractable.