匹伐他汀钙片单、多剂量人体药动学评价

目的:建立LC-MS/MS法测定人血浆中匹伐他汀的浓度,研究其在中国健康受试者体内的单、多剂量药动学过程.方法:20名健康志愿者随机分为2组,每组10人(男女各半),分别口服低、中、高3个剂量(1,2,4 mg)进行单剂量药动学研究,2mg剂量组继续给药(每日1次,连续7 d),进行多剂量药动学研究.采用LC-MS/MS法测定血浆中匹伐他汀的浓度,并采用WinNonLin6.2计算药动学参数.结果:健康受试者单剂量口服1、2、4mg匹伐他汀钙片后的药动学参数:t1/2分别为(11.29±4.28)h、(13.52±5.65)h和(11.87±2.87)h;tmax分别为(0.78±0.32)h、(0.75±0.17)h和(0.93±0.31)h;Cmax分别为(15.80±7.34)ng·ml-1、(36.54±6.29)ng·ml-1和(61.32±15.09)ng·ml-1;AUC(0-48)分别为(36.46±21.86)ng·h·ml-1、(107.90±28.55)ng·h·ml-1和(187.76±62.62)ng·h·ml-1;AUC(0-∞)分别为(40.91±23.20)ng·h·ml-1、(112.97±29.08)ng·h·ml-1和(197.55±68.51)ng·h·ml-1.多剂量组口服2mg匹伐他汀后的药动学参数:t1/2为(13.07±2.16)h,tmax为(0.68±0.12)h,Cmax为(33.88±6.91)ng·ml-1,AUCss为(68.21±20.82)ng·h·ml-1,AUC(0-48)为(77.78±26.50)ng·h·ml-1,AUC(0-∞)为(82.59±26.58)ng·h·ml-1.匹伐他汀钙多次给药达稳态后,药动学参数tmax、t1/2与单次给药一致.结论:在1~4mg剂量范围内匹伐他汀的AUC(0-48)、AUC(0-∞)、Cmax均与剂量呈线性关系;匹伐他汀在连续多次给药后,无体内蓄积现象;匹伐他汀的体内过程在男女性别间无显著差异.

Pharmacokinetics of Pitavastatin with Single and Multiple dose in Chinese Healthy Volunteers

Objective:To develop an LC-MS/MS method for the analysis of pitavastatin in human plasma and study the pharmacokinetics of pitavastatin with single and multiple dose in healthy volunteers.Method:Thirty healthy volunteers were randomly divided into three groups with 5 males and 5 females in each group.The volunteers in the three groups were orally given pitavastatin with single dose 1,2 and 4 mg,respectively,and those with the dose of 2 mg were orally administrated once a day for seven days.The plasma concentrations of pitavastatin were determined by LC-MS/MS method,and its pharmacokinetic parameters were calculated and analyzed by WinNonLin 6.2.Result:The main pharmacokinetic parameters of a single-dose（1,2 and 4 mg）pitavastatin were as follows;t_1/2 of（11.29±4.28）h,（13.52±5.65）hand（11.87±2.87）h,t_maxof（0.78±0.32）h,（0.75±0.17）h and（0.93±0.31）h,C_max of（15.80±7.34）ng · ml^-1,（36.54±6.29）ng · ml^-1and（61.32±15.09）ng · ml^-1.AUC_0-48of（36.46±21.86）ng · h · ml^-1, （107.90±28.55）ng · h · ml^-1and（187.76±62.62）ng · h · ml^-1,AUC_0-8of（40.91±23.20）ng · h · ml^-1,（112.97±29.08）ng · h · ml^-1and（197.55±68.51）ng · h · ml^-1,respectively.The main pharmacokinetic parameters of mutiple-dose（2 mg）pitavastatin were as follows;t_1/2of（13.07±2.16）h,t_maxof（0.68±0.12）h,C_maxof（33.88±6.91）ng · ml^-1,AUC₃₃of（68.21±20.82）ng·h · ml^-1,AUC_0-48of（77.78±26.50）ng · h · ml^-1and AUC_0-48of（82.59±26.58）ng · h · ml^-1.Conclusion: No accumulation occurs after the administration of multiple-dose pitavastatin.AUC_（048）,AUC_（0∞）)and C_maxare increased with the dosage increase of pitavastatin,showing no significant difference in physiological disposition between the male and the female.