Drug-drug interactions that reduce the formation of pharmacologically active metabolites: a poorly understood problem in clinical practice.

Drug-drug interactions can lead to reduced efficacy of medical treatment. Therapeutic failure may for instance result from combined treatment with an inhibitor of the specific pathway that is responsible for the generation of pharmacologically active drug metabolites. This problem may be overlooked in clinical practice. Several examples of drugs will be discussed -clopidogrel, losartan, tamoxifen and codeine - to illustrate differences in the potential impact on drug treatment in clinical practice. We conclude that the combined use of cytochrome P450-blocking serotonin reuptake inhibitors and tamoxifen or codeine should be avoided, whereas the situation is much more complex regarding the use of proton pump inhibitors together with clopidogrel, and the evidence regarding cytochrome P450 inhibitor-dependent activation of losartan is inconclusive.