Pharmacokinetics and metabolism of an alpha,beta-blocker, amosulalol hydrochloride, in mice: biliary excretion of carbamoyl glucuronide.
The pharmacokinetics and metabolism of an alpha,beta-blocker, amosulalol hydrochloride, were investigated in mice. After intravenous administration (10 mg/kg), the plasma concentration of the unchanged drug declined biphasically, with a terminal half-life of 1.1 h. The maximum plasma concentrations were reached at 0.25 h after oral administration, and then declined with apparent half-lives of 0.8-1.3 h. The systemic bioavailability of a 10-mg/kg dose was 38.7%. The area under the plasma concentration curve increased more than proportionally to the dose, which suggests metabolic saturation. After oral and intravenous administrations of (14)C-labelled amosulalol hydrochloride, 64.7% and 81.0% of the radioactivity were recovered, respectively, in the urine within 48 h. HPLC-UV and LC/MS analyses demonstrated that the major urinary metabolite was the glucuronide of M-2 (desmethyl metabolite at the o-methoxyphenoxy group) followed by M-5, the M-3 glucuronide, and the M-4 glucuronide, in that order. In the bile sample, amosulalol carbamoyl glucuronide was found as a new metabolite of this drug.
Drug Metabolism Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., 1-1-8 Azusawa, Itabashi-ku, Tokyo 174-8511, Japan.
Katsuhiro
K
Suzuki
Hidetaka
H
Kamimura
D000317:Adrenergic alpha-Antagonists / Q000378:metabolism / Q000493:pharmacokinetics*; D000319:Adrenergic beta-Antagonists / Q000378:metabolism / Q000493:pharmacokinetics*; D000818:Animals; D019540:Area Under Curve; D001646:Bile / Q000378:metabolism*; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D004983:Ethanolamines / Q000378:metabolism / Q000493:pharmacokinetics*; D005243:Feces / Q000737:chemistry; D020719:Glucuronides / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008813:Mice, Inbred ICR; D013056:Spectrophotometry, Ultraviolet; D000096926:Benzenesulfonamides
D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D004983:Ethanolamines; D020719:Glucuronides; C032473:amosulalol; D000096926:Benzenesulfonamides