The effects of fluvastatin, a CYP2C9 inhibitor, on losartan pharmacokinetics in healthy volunteers.
Losartan is an angiotensin II receptor antagonist that is metabolized by CYP2C9 and CYP3A4 to a more potent antihypertensive metabolite, E3174. Interaction studies with inhibitors of CYP3A4 have not demonstrated significant changes in the pharmacokinetics of losartan or E3174. The authors assessed the steady-state pharmacokinetics of losartan and E3174 when administered alone and concomitantly with fluvastatin, a specific CYP2C9 inhibitor. A prospective, open-label, crossover study was conducted in 12 healthy volunteers with losartan alone and in combination with fluvastatin. The baseline phase 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 AUC0-24 or half-life of losartan or E3174. Losartan apparent oral clearance was not affected by fluvastatin. Inhibition of losartan metabolism appears to require both CYP2C9 and CYP3A4 inhibition.
Meadowcroft
A M
AM
School of Pharmacy, Division of Pharmacotherapy, University of North Carolina at Chapel Hill 27599-7360, USA.
Williamson
K M
KM
Patterson
J H
JH
Hinderliter
A L
AL
Pieper
J A
JA
D000293:Adolescent; D000328:Adult; D000959:Antihypertensive Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases; D001794:Blood Pressure / Q000187:drug effects; D018592:Cross-Over Studies; D065729:Cytochrome P-450 CYP2C9; D065607:Cytochrome P-450 Enzyme Inhibitors; D003971:Diastole; D004244:Dizziness / Q000139:chemically induced; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D005229:Fatty Acids, Monounsaturated / Q000009:adverse effects / Q000494:pharmacology*; D005260:Female; D000077340:Fluvastatin; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000494:pharmacology*; D019808:Losartan / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate; D011446:Prospective Studies; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors*; D013599:Systole
D000959:Antihypertensive Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; D007211:Indoles; D000077340:Fluvastatin; D013250:Steroid Hydroxylases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D039181:Steroid 16-alpha-Hydroxylase; D019808:Losartan