EFFECTS OF ERYTHROMYCIN OR RIFAMPIN ON LOSARTAN PHARMACOKINETICS IN HEALTHY-VOLUNTEERS

Background: Losartan is metabolized by CYP2C9 and CYP3A4 to an active metabolite, E3174, which has greater antihypertensive activity than th e parent compound. Coadministered drugs that inhibit or induce metabol ic processes may therefore alter the pharmacokinetics and pharmacologi c response of losartan and E3174. Objective and Methods: Ten healthy v olunteers were studied to assess the effects of CYP3A4 inhibition and nonspecific P450 enzyme induction on the pharmacokinetics of losartan and E3174. Subjects completed three 1-week phases separated by 6 days: 50 mg losartan every morning, losartan plus 500 mg erythromycin four times a day, and losartan plus 300 mg rifampin (INN, rifampicin) twice a day. On the eighth day of each phase, serial plasma concentrations of losartan and E3174 were obtained over 32 hours and steady-state pha rmacokinetics were determined. Results: Rifampin decreased the area un der the concentration-time curve from time zero to 24 hours after the dose (AUC[0-24]) of losartan by 35% (349 +/- 246 versus 225 +/- 130; p = 0.0001) and decreased the AUC(0-24) of E3174 by 40% (1336 +/- 445 v ersus 792 +/- 302; p < 0.005). Losartan oral clearance was increased b y 44% (p = 0.0001). The half-life values of both compounds were decrea sed by 50% (p < 0.005). In contrast, erythromycin did not significantl y affect the AUC(0-24) or half-life of either losartan or E3174. Concl usions: Rifampin is a potent inducer of losartan and E3174 elimination . Given the magnitude of the effect, this interaction is likely to be clinically significant. On the basis of the minimal inhibitory effects observed with erythromycin, CYP3A4 appears to play a minor role in th e in vivo metabolism of losartan to E3174. Further studies are needed to define the contribution of other isozymes, particularly CYP2C9, to the pharmacokinetics of losartan and E3174.