Pharmacokinetics amlodipine fixed-dose combination amlodipine/benazepril 5/10 mg capsule in healthy volunteers / 中国药学杂志

ABSTRACT

OBJECTIVE: To study the pharmacokinetics amlodipine fixed-dose combination amlodipine/benazepril 5/10 mg capsule in healthy volunteers and to provide evidence for its clinical application. METHODS: Twenty-four healthy volunteers were divided to 3 groups with male and female half by half randomly, a single oral dose 1, 2, 3 capsules (5, 10 or 15 mg amlodipine respectively) was given to 8 healthy volunteers and 14 d consecutive administration (Qd) multiple oral doses 2 capsules (10 mg amlodipine) were given to the 8 healthy volunteers the mid-dose group in this open randomized design. Plasma concentration amlodipine was determined by ultra performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLCESI-MS/MS), the main pharmacokinetic parameters were calculated by DAS2.0 program using non compartment analysis (published by Mathematical Pharmacology Professional Committee China, Shanghai, China). RESULTS: After the healthy volunteers received a single dose 1, 2, 3 capsules (5, 10, 15 mg amlodipine), the main pharmacokinetic parameters amlodipine were as follows t1/2 were (33.5 ± 6.2), (36.1 ± 7.6), (39.8 ± 12.5) h; tmax were (6.0 ± 1.1), (7.0 ± 3.4), (5.6 ± 3.0) h; ρmax (4.37 ± 1.37), (7.23 ± 1.81), (14.71 ± 3.14) ng · mL-1; AUC0→144 were (167.7 ± 35.9), (283.8 ± 47.6), (574.9 ± 159.0) ng · h · mL-1; AUC0→∞ were (176.8 ± 40.2), (304.1 ± 54.8), (628.2 ± 197.5) ng · h · mL-1; V/F were (1 389.6 ± 231.5), (1 724.4 ± 269.2), (1 414.2 ± 342.6) L; MRT0-144 were (47.8 ± 4.0), (51.1 ± 9.9), (52.9 ± 13.9) h; CL/F were (29.5 ± 6.5), (34.0 ± 7.2), (25.9 ± 7.6) L · h-1, respectively. In the dose profile 5-15 mg, AUC0→144, AUC0-∞ and ρmax amlodipine increased with dose, but not proportionally; the statistical results showed that t1/2, V/F, CL/F, MRT0-144 and tmax had no significant difference (P > 0.05) between three groups, whereas there were increasing tendency t1/2 and MRT0-144 between three groups, the t1/2 values single high dose group increased by 6 and 3 h compared with single middle and low dose groups. Steady state concentration was achieved after 14 d consecutive administration test drug, ρmaxss was (24.03 ± 5.56) ng · mL-1, ρminss was (15. 64 ± 3.93) ng · mL-1, AUC0~24ss was (463.7 ± 121.1) ng · h · mL-1 and DF was (0.4 ± 0.1), respectively. Statistical analys is indicated that these ρmax, AUC0-24ss values multiple dose group were obviously higher than the ρmax, AUC0-∞ the single 10 mg dose group with p values less than 0.05 which confirmed that obvious accumulation amlodipine in human plasma occurred after multiple doses administration. CONCLUSION: The established UPLC-ESI-MS/MS method is simple, rapid, sensitive and accuracy, and can be used for the study clinical pharmacokinetics of amlodipine. The dynamics amlodipine in vivo are nonlinear in the dosage 5-15 mg, no gender difference is found in the main pharmacokinetic parameters amlodipine, and there is obvious accumulation amlodipine besylate in human plasma found after repeated administration. Amlodipine besylate is well tolerated and no serous adverse reaction is observed during the trail.