The Comparative Study On Pharmacokinetics Of R- And S- Isomers Of NBP In Beagle Dogs

Objectives: To study the pharmacokinetics of S-NBP and S,R-NBP in Beagle dogs, and compare their pharmacokinetic characteristics. The absolute bioavailability were evaluated after oral and iv S-NBP kinetics test respectively. Pharmacokinetic profiles of S-NBP and R-NBP were studied in Beagle dogs after oral administration of both enantiomer and racemate of NBP, in order to provide a reference for clinical test and the development of NBP.Methods: A sensitive NP-HPLC method which was based on CSP method for split optical isomers was developed and validated for the determination of NBP enantiomers in the comparative pharmacokinetics study in Beagle dogs for the first time. The absolute bioavailability were calculated after the oral administration and iv administration, respectively. After the separation of NBP enantiomers with a Chiralcel OD-H column the analytical method was verified with the correlation between the determine-effect and the concentration, sample recovery, precision, accuracy and stability in the active standard.Results: Serum concentration reached the peak levels within 1.92±1.28 h after oral S-NBP at dose of 40 mg·kg^-1 in Beagle dogs. The main pharmacokinetic parameters were 0.79±0.17μg·ml^-1, 2.00±0.68 h, 2.70±0.43μg·h·ml^-1 for Cmax,t_1/2β and AUC_0-10h respectively.The pharmacokinetic parameters after oral administration of 80 mg·kg^-1 S,R-NBP ( containing 40 mg·kg^-1 S-NBP and R-NBP ) calculated from the serum concentration data were following: The Tpeak of S-NBP was 2.42±1.11h; the average of Cmax was 0.70±0.33μg·ml^-1; and the elimination half-life (t_1/2β) of S-NBP was about 2.56±0.51 h. The Tpeak of R-NBP was 2.42±1.11h; the average of Cmax was 1.00±0.41 ug·ml^-1; and the elimination half-life (t_1/2β) of R-NBP was 2.87±0.67 h.The results of iv experiment indicated that the serum concentration of S-NBP decreased quickly. The calculated pharmacokinetic parameters were 2.37±0.74 h, 1.54±0.16 ug·h·ml^-1 for t_1/2β and AUC_0-5h. After dose-corrected the absolute bioavailability was 45.7±4.7%.Paired t-tests indicated that there was no significant difference between the results of oral S-NBP and S,R-NBP in Cmax, AUC_0-10h, Tpeak, t_1/2βand MRT_0-10h. On the whole, it can be considered that NBP enantiomers seldom transformed each other in vivo in Beagle dogs.Conclusion: There were similar pharmacokinetic characteristics of S-NBP after oral S-NBP and S,R-NBP (the same content of S-NBP). NBP enantiomers seldom transform each other in vivo in Beagle dogs. The absolute bioavailability was 45.7 %.