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Enantioselective disposition of clenbuterol in rats

2013; Wiley; Volume: 35; Issue: 4 Linguagem: Inglês

10.1002/bdd.1885

1099-081X

Iori Hirosawa, Mai Ishikawa, Mio Ogino, Hiroshi Ito, Takuya Hirao, Harumi Yamada, Mariko Asahi, Hajime Kotaki, Yoshimichi Sai, Ken–ichi Miyamoto,

Asthma and respiratory diseases

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. Copyright © 2013 John Wiley & Sons, Ltd.