The Pharmacokinetics And Chiral Inversion Research Of R-bambuterol In Rats And Beagle Dogs

Bambuterol(BMB), a long-acting β2-adrenoceptor agonists anti-asthmatic drug, is the prodrug of terbutaline(TBT). BMB is a chiral drug and currently on the market as a racemic mixture(Rac-BMB) consisting of 50% R-BMB(eutomer) and 50% S-BMB(distomer). R-BMB is the therapeutically active, R & D R-BMB to replace Rac-BMB can show a higher anti-asthmatic potency. We have studied the pharmacokinetics and chiral inversion of R-BMB after intravenous, oral administration in rats and beagle dogs, to better understand the preclinical pharmacokinetic properties of R-BMB and to provide reference for its future clinical application. The main contents of this research are as follow:1) Established a LC-MS/MS analysis method for the determination of BMB and its major metabolites in biological samples. This method performed good selectivity and the calibration curves in the range 0.5 ~ 1000 ng/m L were linear, the lowest limit of quantification was 0.50 ng/m L, the accuracy, precision and stability were in line with the requirements.2) After intravenous injection of R-BMB in rats and beagle dogs, the drug concentration declined fast in plasma in an initial short period of time, then declined slowly. After oral administration low, medium and high doses of R-BMB in rats and beagle dogs. The results show that R-BMB was absorbed quickly in rats and beagle dogs, the Tmax was about 2 h. In the selected doses range of this study, the Cmax and AUC of R-BMB presented linear correlation with doses, the Tmax, CL, t1/2, V and other pharmacokinetic parameters were independent on the administration doses, R-BMB shown linear pharmacokinetic profile. The bioavailability of R-BMB in rats and beagle dogs were 49.7% and 74.6%, respectively. The bioavailability of R-BMB in rats was significantly lower than that in beagle dogs which indicates some differences in bioavailability between species. After intravenous, oral administration of R-BMB and Rac-BMB in rats and beagle dogs, the pharmacokinetic parameters(Tmax, t1/2, CL, V) of R-BMB and Rac-BMB were equivalent. After oral administration of R-BMB, S-BMB in rats, no significant difference of the mass of drug and its main metabolites in bile were observed between R-BMB and S-BMB groups.3) 1.84%、3.91%、1.36% of chiral inversion were detected in plasma, bile and urine after oral administration of R-BMB in rats, 4.47%、2.96%、1.46% of chiral inversion were detected in plasma, bile and urine after oral administration of S-BMB. Meanwhile, 4.17% of chiral inversion were detected in plasma after oral administration of R-BMB in beagle dogs, 3.10% of chiral inversion were detected in plasma after oral administration of S-BMB in beagle dogs. Furthermore, chiral inversion of BMB and its main metabolites TBT enantiomers were negligible after incubation in rat hepatocyte suspensions or buffers at different p Hs, which suggests that the in vivo chiral inversion of BMB and TBT enantiomers were not triggered by hepatocyte enzymes and p H.