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

J Clin Pharmacol. 1999 Apr;39(4):418-24. doi: 10.1177/00912709922007886.

Abstract

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.

Publication types

  • Clinical Trial
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Antihypertensive Agents / adverse effects
  • Antihypertensive Agents / pharmacokinetics*
  • Area Under Curve
  • Aryl Hydrocarbon Hydroxylases*
  • Blood Pressure / drug effects
  • Cross-Over Studies
  • Cytochrome P-450 CYP2C9
  • Cytochrome P-450 Enzyme Inhibitors*
  • Diastole
  • Dizziness / chemically induced
  • Drug Interactions
  • Enzyme Inhibitors / adverse effects
  • Enzyme Inhibitors / pharmacology*
  • Fatty Acids, Monounsaturated / adverse effects
  • Fatty Acids, Monounsaturated / pharmacology*
  • Female
  • Fluvastatin
  • Gastrointestinal Diseases / chemically induced
  • Humans
  • Indoles / adverse effects
  • Indoles / pharmacology*
  • Losartan / adverse effects
  • Losartan / blood
  • Losartan / pharmacokinetics*
  • Male
  • Metabolic Clearance Rate
  • Prospective Studies
  • Steroid 16-alpha-Hydroxylase*
  • Steroid Hydroxylases / antagonists & inhibitors*
  • Systole

Substances

  • Antihypertensive Agents
  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Fatty Acids, Monounsaturated
  • Indoles
  • Fluvastatin
  • Steroid Hydroxylases
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Aryl Hydrocarbon Hydroxylases
  • Steroid 16-alpha-Hydroxylase
  • Losartan