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

Abstract

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.

• Authors: M R Goldberg, M W Lo, P J Deutsch, S E Wilson, E J McWilliams, J B McCrea
• Journal: Clinical pharmacology and therapeutics (Clin Pharmacol Ther) Vol. 59 Issue 3 Pg. 268-74 (Mar 1996) ISSN: 0009-9236 [Print] United States
• PMID: 8653989 (Publication Type: Clinical Trial, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

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