Pharmacokinetics Of Amlodipine Besylate In Rat And Human Body

1.Studies on the stereoselective pharmacokinetics and the chiral inversion of Amlodipine besylate in Wistar rat plasmaA chiral liquid chromatography method to determine the enantiomers of Amlodipine besylate in Wistar rat plasma was established. A Chiralcel OD-RH(0.46(?)×15cm)column with a mobile phase composed of acetonitrile-0.05mol.L-1 KPF6- triethylamine in the ratio 25:75:0.3 (v/v) was used in separation. The biological samples were analysed after liquid-liquid extraction, The calibration curve of enantiomers of amlodipine in plasma have a good linear between 2.0-100.0ng·mL-1. The intra-day and inter-day QC samples expressed as relative standard deviation(RSD),were no more than 10.6%, respectively,while accuracy were-5.20%-6.50%interms of relative error (RE). Stereoselective pharmacokinetics and the chiral inversion were studied of amlodipine enantiomer after a single oral administration at a dose of 4.0 mg·kg-1 to Wistar rats. The result showed the plasma levels for R-amlodipine were always higher than its antipode in six Wistar rats’ plasma. The mean Cmax,AUC0-t and AUC0-∞values for R-amlodipine were 1.15、1.27and1.37 times of those of S-amlodipine respectively, indicating that the pharmacokinetics of Amlodipine besylate in Wistar rats was stereoselective. And through monitoring the concentration of S-amlodipine in Wistar rat plasma, it was certificated that the chiral inversion of amlodipine besylate could not occur in Wistar rats.2. Studies on tissue distribution of Amlodipine besylate and its two enantiomers in miceA chiral liquid chromatography method to determine the enantiomers of Amlodipine besylate tissue distribution in mice after a single oral administration at a dose of 5.6mg·kg-1 to mices.The R-amlodipine concentration was 1.17 times as high as S-amlodipine in the major absorption organs such as small intestine, in the target organ heart The S-amlodipine concentration was higher than R-amlodipine, in kidney, and liver, the major excretion organs, the results were exactly the different as in the heart. The experiment indicted that differences between enantiomers are significant for the distributions in mice tissue.3.The pharmacokinetics of Levamlodipine in human plasmaA LC-MS/MS method has been established for determination levamlodipine in human plasma.Zorbax EclipseC18-Column(150mm×4.6mm,5μm,Agilent Technologies). With mobile phase consisted of a mixture of methanol:1%formic acid (85:15 v/v) was used in separation.Multiple reaction monitoring(MRM) adopting the precursor to product transitions of m/z 409.2→m/z 238.2 and m/z 347.1→m/z195.1. The calibration curve in plasma was linear between 0.10～20.0ng·mL-1. The intra-day and inter-day QC samples,expressed as relative standard deviation(RSD),were no more than 15%, respectively,while accuracy were less than±4%in terms of relative error (RE).A single oral dose of 5mg Levamlodipine test and reference preparations were administrated to healthy volunteers to study pharmacokinetics and relative bioavailability of levamlodipine tablets in healthy male volunteers. Main pharmacokinetic parameters for single dose were as follows:Tmax 7.8±2.67 h and 7.00±2.00h;Cmax:3.02±0.99 ng·mL-1 and 3.17±0.93 ng·mL-1;AUC0-120:114.1±28.9ng·h·mL-1 and 120.9±32.1ng·h·mL-1;AUC0-∞:134.0±36.4 ng·h·mL-1 and150±50.7 ng·h·mL-1.The pharmacokinetic parameters were calculated by DAS2.0 program, The optimal compartment model fitted to two-compartment model.