The effects of fluvastatin, a CYP2C9 inhibitor, on losartan pharmacokinetics in healthy volunteers

Losartan is an angiotensin II receptor antagonist that is metabolized by CY P2C9 and CYP3A4 to a more potent antihypertensive metabolite, E3174. Intera ction studies with inhibitors of CYP3A4 have not demonstrated significant c hanges in the pharmacokinetics of losartan or E3174. The authors assessed t he steady-state pharmacokinetics of losartan and E3174 when administered al one and concomitantly with fluvastatin, a specific CYP2C9 inhibitor. A pros pective, open-label, crossover study was conducted in 12 healthy volunteers with losartan alone and in combination with fluvastatin. The baseline phas e was 7 days of losartan (50 mg QAM), and the inhibition phase was 14 total days of fluvastatin (40 mg QHS), with the final 7 days including losartan. The authors found that fluvastatin did not significantly change the steady -state AUC(0-24) or half-life of losartan or E3174. Losartan apparent oral clearance was not affected by fluvastatin. Inhibition of losartan metabolis m appears to require both CYP2C9 and CYP3A4 inhibition. (C) 1999 the Americ an College of Clinical Pharmacology.