title: Enantioselective disposition of clenbuterol in rats.
abstract: 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 0.1 ml volumes of plasma were precisely quantified at concentrations as low as 0.25 ng/ml. The pharmacokinetic profiles of clenbuterol enantiomers following intravenous and intraduodenal administration of clenbuterol racemate (2 mg/kg) in rats were significantly different. The distribution volume of (-)-R-clenbuterol (9.17 l/kg) was significantly higher than that of (+)-S-clenbuterol (4.14 l/kg). The total body clearance of (-)-R-clenbuterol (13.5 ml/min/kg) was significantly higher than that of the (+)-S-enantiomer (11.5 ml/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.
authors: School of Pharmaceutical Science, International University of Health and Welfare, 2600-1 Kitakanemaru, Ohtawara, Tochigi, 324-8501, Japan; Graduate School of Natural Science and Technology, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan.
authors: Iori
authors: I
authors: Hirosawa
authors: Mai
authors: M
authors: Ishikawa
authors: Mio
authors: M
authors: Ogino
authors: Hiroshi
authors: H
authors: Ito
authors: Takuya
authors: T
authors: Hirao
authors: Harumi
authors: H
authors: Yamada
authors: Mariko
authors: M
authors: Asahi
authors: Hajime
authors: H
authors: Kotaki
authors: Yoshimichi
authors: Y
authors: Sai
authors: Ken-Ichi
authors: K
authors: Miyamoto
mesh_terms: D000318:Adrenergic beta-Agonists / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000652:urine; D000818:Animals; D001646:Bile / Q000737:chemistry; D001798:Blood Proteins / Q000378:metabolism; D002976:Clenbuterol / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000652:urine; D008297:Male; D011485:Protein Binding; D017208:Rats, Wistar; D013237:Stereoisomerism; D014018:Tissue Distribution
chemical_list: D000318:Adrenergic beta-Agonists; D001798:Blood Proteins; D002976:Clenbuterol
keywords: clenbuterol; enantiomer; excretion; pharmacokinetics; protein binding