Clenbuterolのラットにおける体内動態の光学特異性

13301甲第4069号博士（薬学）金沢大学博士論文要旨Abstract 以下に掲載：Biopharmaceutics and Drug Disposition 35(4) pp.207-217.Wiley Online Library 共著者：Iori Hirosawa, Mai Ishikawa, Mio Ogino, Hiroshi Ito, Takuya Hirao, Harumi Yamada, Mariko Asahi, Hajime Kotaki, Yoshimichi Sai, Ken-ichi Miyamot

Enantioselective disposition of clenbuterol in rats

Clenbuterol is a long-acting β2-adrenoceptor agonist and bronchodilator that is used for the treatment of asthma, but the desired activities reside almost exclusively in the (-)-R-enantiomer. This study examined enantioselectivity in the disposition of clenbuterol following administration of clenbuterol racemate to rats. Concentrations of clenbuterol enantiomers in plasma, urine and bile were determined by LC-MS/MS assay with a Chirobiotic T column. This method was confirmed to show high sensitivity, specificity and precision, and clenbuterol enantiomers in 0.1ml volumes of plasma were precisely quantified at concentrations as low as 0.25ng/ml. The pharmacokinetic profiles of clenbuterol enantiomers following intravenous and intraduodenal administration of clenbuterol racemate (2mg/kg) in rats were significantly different. The distribution volume of (-)-R-clenbuterol (9.17l/kg) was significantly higher than that of (+)-S-clenbuterol (4.14l/kg). The total body clearance of (-)-R-clenbuterol (13.5ml/min/kg) was significantly higher than that of the (+)-S-enantiomer (11.5ml/min/kg). An in situ absorption study in jejunal loops showed no difference in the residual amount between the (-)-R- and (+)-S-enantiomers. Urinary clearance was the same for the two enantiomers, but biliary excretion of (-)-R-clenbuterol was higher than that of the (+)-S-enantiomer. The fractions of free (non-protein-bound) (-)-R- and (+)-S-clenbuterol in rat plasma were 48.8% and 33.1%, respectively. These results indicated that there are differences in the distribution and excretion of the clenbuterol enantiomers, and these may be predominantly due to enantioselective protein binding. © 2013 John Wiley & Sons, Ltd.発行後1年より全文公