Enantioselective Pharmacokinetics of Bambuterol in Preclinical Species : Does S-bambuterol Influence the Clearance of the R-antipode ?

In a comprehensive preclinical program, Guan et al. systematically investigated and reported the pharmacokinetics of R-bambuterol and racemic bambuterol (non-stereoselective assay) after the administration intravenous and multiple single oral doses administration of either R-bambuterol or the racemate [1]. Although the drug used in therapy is the racemic mixture of the two enantiomers of bambuterol, the understanding of the disposition of the active enantiomer in either humans or animals was hitherto non-existent. Since bambuterol belongs to the class of b2-adrenergic agonists (sympathomimetic amines) that are known to exhibit the entire pharmacological activity via the R-enantiomers, while the S-enantiomers are devoid of pharmacodynamic activity [2], this preclinical investigation paying attention to the pharmacokinetics of the active enantiomer, R-bambuterol, was timely [1]. The intent of the report is to bring into perspectives a few observations that may have a bearing in completely understanding the pharmacokinetics and disposition of bambuterol enantiomers. To be concise, the discussion in this report with regard to the pharmacokinetic anomaly will be restricted to the intravenous pharmacokinetics of bambuterol which was gathered in rats and dogs. The first major limitation in the study was related to the lack of delineation of the pharmacokinetics of the S-bambuterol, and therefore, the representation of pharmacokinetics of rac-bambuterol would be ambiguous without knowing the individual contribution of each of the two enantiomers [1]. For instance, the systemic clearance of R-bambuterol in rats (7.8 mL/min/kg) was higher in comparison to the value obtained for rac-bambuterol (5 mL/min/kg). Therefore, the observed 1.56-fold slower clearance for rac-bambuterol suggested that either S-bambuterol may impede the clearance of the R-enantiomer or S-bambuterol may have a much slower clearance as compared to the R-enantiomer. Akin to the rats, the systemic clearance of R-bambuterol (20.1 mL/min/kg) in dogs was higher as compared to the value obtained for rac-bambuterol (16.7 mL/min/kg) [1]. Also, similar interpretation of the likely influence of S-bambuterol on the clearance of the R-bambuterol was judged with the pharmacokinetic data in the dogs, although the difference in clearance was 1.2-fold between rac-bambuterol vs R-bambuterol [1]. Similar to the observations of systemic clearance, the volume of distribution at steady state (VSS) of R-bambuterol vs rac-bambuterol exhibited differences in rats and dogs (1.7and 1.3-fold higher VSS noted for R-bambuterol vs rac-bambuterol in rats and dogs, respectively). Therefore, it appeared that lack of the availability of S-bambuterol pharmacokinetic data from the rac-bambuterol would make it difficult to unambiguously interpret the data observed for both the clearance and VSS gathered in this study [1]. Such influence of one enantiomer over the clearance of the other enantiomer has been documented for drugs such as methylphenidate, verapamil, and propranolol. In case of methylphenidate enantiomers, the presence of D-methylphenidate significantly increased the clearance of L-methylphenidate in children with attention-deficit/hyperactivity disorder [3]. The clearance of S-verapamil was consistently showed to be at least twofold greater than R-verapamil in healthy human subjects of stratified age & Nuggehally R. Srinivas srini.suramus@yahoo.com