PHARMACOKINETIC DRUG-INTERACTIONS WITH ANTIMICROBIAL AGENTS

As new classes of antimicrobial drugs have become available, and new u ses found for older drugs, pharmacokinetic drug interactions with anti microbials have become more common. Macrolides, fluoroquinolones, rifa mycins, azoles and other agents can interact adversely with commonly u sed drugs, usually by altering their hepatic metabolism. The mechanism s by which antimicrobial agents alter the biotransformation of other d rugs is increasingly understood to reflect inhibition or induction of specific cytochrome P450 enzymes. Macrolides inhibit cytochrome P450II IA4 (CYP3A4), which appears to be the most common metabolic enzyme in the human liver and is involved in the metabolism of many drugs, inclu ding cyclosporin, warfarin and terfenadine. Some quinolones preferenti ally inhibit CYP1A2, which is partially responsible for methylxanthine metabolism. Azoles appear to be broad spectrum inhibitors of cytochro mes P450. Within each of these antibiotic classes, there is a rank ord er of inhibitory potency towards specific cytochrome P450 enzymes. By contrast, rifampicin (rifampin) and rifabutin induce several cytochrom es P450, including CYP3A4, and hence can enhance the metabolism of man y other drugs. By using in vitro preparations of human enzymes it is i ncreasingly possible to predict those antibiotics that will adversely affect the metabolism of other drugs. In addition, between-patient var iability in frequency of interaction may relate to differences in the activities of these enzymes. Although the mechanisms and scope of thes e interactions are becoming well characterised, the remaining challeng e is how to best inform the clinician so that the undesirable conseque nces of interactions may be prevented.