Phenobarbital minimally alters plasma concentrations of losartan and its active metabolite E-3174

Clin Pharmacol Ther. 1996 Mar;59(3):268-74. doi: 10.1016/S0009-9236(96)80004-X.


Losartan, a selective angiotensin II (AT1) receptor antagonist for hypertension, is metabolized to an active carboxylic acid metabolite, E-3174, which has a longer half-life. To investigate the effects of induction of cytochrome P450 on the metabolism of losartan, we evaluated the effects of phenobarbital on the plasma profiles of losartan and E-3174 in 15 healthy male subjects. Ten subjects received a single 100 mg oral dose of losartan before and during phenobarbital administration (100 mg/day for 16 days), and five subjects received losartan before and during placebo. Urinary excretion of 6-beta-hydroxycortisol (relative to 17-hydroxycorticosteroids) was measured as an endogenous marker of cytochrome P450 induction. The geometric mean area under the plasma concentration-time curve ratios (with/without phenobarbital and 90% confidence intervals) for losartan and its metabolite (E-3174) were 0.795 (0.723, 0.875) and 0.799 (0.778, 0.820), respectively, indicating that phenobarbital treatment significantly but to a clinically minor extent reduced plasma concentrations of losartan and E-3174 (p<0.01). Half-life values of losartan and E-3174 were unchanged. The ratio of 6-beta-hydroxycortisol to 17-hydroxycorticosteroids doubled in the phenobarbital group (p < 0.001) and did not change appreciably in the placebo group.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anticonvulsants / pharmacology
  • Antihypertensive Agents / blood
  • Antihypertensive Agents / pharmacokinetics*
  • Biphenyl Compounds / blood
  • Biphenyl Compounds / pharmacokinetics*
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / biosynthesis
  • Enzyme Induction / drug effects
  • Humans
  • Hydrocortisone / analogs & derivatives
  • Hydrocortisone / urine
  • Hypnotics and Sedatives / pharmacology
  • Imidazoles / blood*
  • Imidazoles / pharmacokinetics*
  • Losartan
  • Male
  • Mixed Function Oxygenases / biosynthesis
  • Phenobarbital / pharmacology*
  • Reference Values
  • Single-Blind Method
  • Tetrazoles / blood*
  • Tetrazoles / pharmacokinetics*


  • Anticonvulsants
  • Antihypertensive Agents
  • Biphenyl Compounds
  • Hypnotics and Sedatives
  • Imidazoles
  • Tetrazoles
  • 6 beta-hydroxycortisol
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • losartan carboxylic acid
  • Losartan
  • Hydrocortisone
  • Phenobarbital