甲磺酸雷沙吉兰在中国健康志愿者中药动学药效学的分析-analysis of pharmacokinetics and pharmacodynamics of rasagiline mesylate in chinese healthy volunteers.docx

The study of influencing factors on pharmacokinetics and pharmacodynemics of rasagiline mesylate in healthy volunteersAbstractObjective: An assay on Chinese healthy subjects was undertaken to investigate pharmacodynamics and pharmacokinetics of rasagiline mesylate. We discussed the effects of pharmacodynamics and pharmacokinetics while concerning genetic, gender and diet. The aim was to provide the basis for clinical rational use of drug.Method: 30 healthy volunteers (the ratio of males and females was no less than 1:3)with informed consent were enrolled in the study.In pharmacokinetics study, objects were grouped by doses as follows:0.5mg, 1.0mg and 2.0mg for single-dose study, parallel design. Plasma samples were collected before and after administration at different times. Multiple-dose study was employed after single-dose study in medial-dose group. With a washout period, the assay of high-fat diet group was started with 2mg rasagiline. UPLC-MS/MS was adopted to evaluate the concentration of rasagiline in plasma. And the pharmacokinetic parameters were calculated with DAS2.0.The inhibition of MAO-B activity in platelet and the area under the inhibition curve were supposed to be used to study pharmacodynamics. Grouping method was the same as pharmacokinetics study. Activity of MAO-B in platelets was assayed by the spectrofluorimetric method. Inhibition ratio of MAO-B activity was calculated by the variation of MAO-B activity before and after administration.The genotype of CYP1A2（-163CA）mutations, which was deemed as geneticfactor,wasdetectedwithpolymerasechainreaction-restrictionfragmentlength polymorphism(PCR-RFLP).Result: (1) The pharmacokinetics assay of rasagiline mesylate demonstrated that Cmax and AUC0-t were in accord with the feature of linear pharmacokinetic over the dosage range of 0.5mg-2.0mg (R2 were 0.589 and 0.822, respectively). The pharmacokinetic parameters between single-dose and multi-dose assays were notstatistically significant（P 0.05