Phenobarbital minimally alters plasma concentrations of losartan and its active metabolite E-3174.
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.
Goldberg
M R
MR
Division of Clinical Pharmacology, Merck Research Laboratories, West Point, PA 19486, USA.
Lo
M W
MW
Deutsch
P J
PJ
Wilson
S E
SE
McWilliams
E J
EJ
McCrea
J B
JB
D000328:Adult; D000927:Anticonvulsants / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000097:blood / Q000493:pharmacokinetics*; D001713:Biphenyl Compounds / Q000097:blood / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives / Q000652:urine; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D007093:Imidazoles / Q000097:blood* / Q000493:pharmacokinetics*; D019808:Losartan; D008297:Male; D006899:Mixed Function Oxygenases / Q000096:biosynthesis; D010634:Phenobarbital / Q000494:pharmacology*; D012016:Reference Values; D016037:Single-Blind Method; D013777:Tetrazoles / Q000097:blood* / Q000493:pharmacokinetics*
D000927:Anticonvulsants; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D006993:Hypnotics and Sedatives; D007093:Imidazoles; D013777:Tetrazoles; C001380:6 beta-hydroxycortisol; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C066026:losartan carboxylic acid; D019808:Losartan; D006854:Hydrocortisone; D010634:Phenobarbital