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目的:阐明健康志愿受试者经单次和多次餐时口服盐酸伊伐布雷定片后,原型药伊伐布雷定、代谢产物去甲伊伐布雷定(S-18982)的体内动态变化规律及其对心率和心率-收缩压乘积的影响。方法:(1)采用随机、开放、自身交叉设计的研究方法。12名受试者交叉单次餐时口服盐酸伊伐布雷定片5、10和15 mg,采集给药前及给药后0.25、0.5、0.75、1、1.5、2、2.5、3、4、6、8、12、24、36和48 h血样。单次给药结束后12名受试者分别于早、晚餐时用药各5 mg,连续5 d(共9次),采集第3~5天早上用药前、第5天早上用药后(按单次给药时间点)血样。用LC-MS/MS法测定伊伐布雷定和S-18982血药浓度,DAS 3.0计算药代参数并评价药物蓄积性。(2)采集单次给药各周期和多次给药第5天给药前及给药后24 h内心率和血压,进行药效分析。结果:(1)单次给药5、10和15 mg后,原型药及S-18982的C_(max)分别为(18±7)、(36±18)和(45±24)μg/L,(2.6±0.8)、(4.9±1.9)和(6.9±1.7)μg/L;AUC0-48 h分别为(55±20)、(124±47)和(186±79)μg·h·L~(-1),(15±4)、(35±9)和(57±15)μg·h·L~(-1)。原型药和S-18982的t_(max)、t1/2分别在1.5~1.9 h、2.3~2.9 h和1.8~2.4 h、8.0~9.3 h范围内。多次给药5 mg后原型药和S-18982的C_(max)、AUC_(0-48 h)分别为(21±9)、(78±31)μg/L和(3.6±1.3)、(34±14)μg·h·L~(-1)。(2)药物对受试者心率和心率-收缩压乘积都有降低作用且呈剂量依赖性,给药后约3 h(比t_(max)延迟约1~2 h)时作用最强,可持续至9~12 h。结论:(1)餐时给药条件下单次给药伊伐布雷定及其代谢产物S-18982的吸收程度C_(max)和AUC_(0-48 h)在5~15 mg剂量范围内呈线性规律;原型药吸收达峰较S-18982略快,消除较S-18982快。多次给药后两物质血浆浓度与单次给药相比有所提高,但均无明显蓄积情况发生。(2)盐酸伊伐布雷定片可降低健康受试者心率、心率-收缩压乘积,对收缩压影响较小。
OBJECTIVE: To elucidate the in vivo dynamic changes of the ibuprofen and metformin (S-18982), a prototype drug, after oral administration of ivabradine hydrochloride tablets in healthy volunteers after single or multiple meals. And its impact on heart rate and heart rate - systolic pressure product. Methods: (1) Using random, open, self-crossing design of research methods. Twelve subjects were orally administered with 5, 10 and 15 mg of ivabradine hydrochloride tablets orally at a single crossover meal before and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 6, 8, 12, 24, 36 and 48 h blood samples. After the single administration, 12 subjects took 5 mg for 5 days each at morning and evening for 9 consecutive days, and collected the morning before treatment and the morning after treatment on the fifth day Time of administration) blood sample. Plasma concentrations of ivabradine and S-18982 were determined by LC-MS / MS. DAS 3.0 was used to calculate pharmacokinetic parameters and evaluate drug accumulation. (2) To collect the pharmacodynamics analysis of heart rate and blood pressure within the first 24 hours after administration of each cycle of single administration and multiple administration on the fifth day. Results: (1) After single administration of 5, 10 and 15 mg, the Cmax of prototype and S-18982 were (18 ± 7), (36 ± 18) and (45 ± 24) μg / L , (2.6 ± 0.8), (4.9 ± 1.9) and (6.9 ± 1.7) μg / L respectively; AUC0-48 h were (55 ± 20), (124 ± 47) and (186 ± 79) μg · h · L ~ (-1), (15 ± 4), (35 ± 9) and (57 ± 15) μg · h · L -1, respectively. The t_ (max) and t1 / 2 of the prototype drug and S-18982 ranged from 1.5 to 1.9 h, from 2.3 to 2.9 h and from 1.8 to 2.4 h, from 8.0 to 9.3 h, respectively. The C max and AUC 0-48 h of prototype and S-18982 after repeated administration of 5 mg were (21 ± 9), (78 ± 31) μg / L and (3.6 ± 1.3), respectively 34 ± 14) μg · h · L -1. (2) The drug had a dose-dependent and dose-dependent decrease in the product of heart rate and heart rate-systolic blood pressure, and the effect was the strongest at about 3 h (about 1 to 2 h later than t max) Lasts until 9 ~ 12 h. Conclusions: (1) Cmax and AUC 0-48 h of single dose of ivabradine and its metabolite S-18982 under the condition of mealtime were within the range of 5-15 mg Linear rule; prototype drug absorption peaks slightly faster than the S-18982, eliminating faster than the S-18982. After multiple administrations, the plasma concentrations of the two substances increased compared with the single administration, but no significant accumulation occurred. (2) The ivabradine hydrochloride tablets can reduce the healthy subjects heart rate, heart rate - systolic blood pressure product, less impact on systolic blood pressure.