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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,2 mg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WinNonLin 6.2计算药动学参数。结果:健康受试者单剂量口服1、2、4 mg匹伐他汀钙片后的药动学参数:t_(1/2)分别为(11.29±4.28)h、(13.52±5.65)h和(11.87±2.87)h;t_(max)分别为(0.78±0.32)h、(0.75±0.17)h和(0.93±0.31)h;C_(max)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2 mg匹伐他汀后的药动学参数:t_(1/2)为(13.07±2.16)h,t。。为(0.68±0.12)h,C★;为(33.88±6.91)ng·ml～,AUC,:为(68.21±20.82)ng·h·ml～,AUC(048)为(77.78±±26.50)ng·h·ml～,AUC(0.。)为(82.59±26.58)ng·h·ml～。匹伐他汀钙多次给药达稳态后,药动学参数t～、t1/2与单次给药一致。结论:在1～4 mg剂量范围内匹伐他汀的AUC(。。8)、AUC(吣)、C～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。
OBJECTIVE: To establish a method for the determination of pitavastatin in human plasma by LC-MS / MS and study its single and multi-dose pharmacokinetics in Chinese healthy volunteers. Methods: Twenty healthy volunteers were randomly divided into two groups (10 males and 10 females). Each group was given low dose, middle dose and high dose (1, 2, and 4 mg) mg dose group continue to be administered (once daily for 7 consecutive days), multi-dose pharmacokinetic studies. Plasma concentrations of pitavastatin were determined by LC-MS / MS and pharmacokinetic parameters were calculated using WinNonLin 6.2. Results: The pharmacokinetic parameters of healthy volunteers after a single oral dose of 1,2,4 mg pitavastatin calcium tablets were (11.29 ± 4.28) h, (13.52 ± 5.65) h and ( 11.87 ± 2.87 h and t max respectively were (0.78 ± 0.32) h, (0.75 ± 0.17) h and (0.93 ± 0.31) h respectively, and C max were (15.80 ± 7.34) ng · ml ~ (- (36.56 ± 21.86) ng · ml ~ (-1) and (61.32 ± 15.09) ng · ml ~ (-1) respectively; AUC_ (0-48) (-1), (107.90 ± 28.55) ng · h · ml ~ (-1) and (187.76 ± 62.62) ng · h · ml ~ (-1) respectively, and the AUC_ (0_∞) were (40.91 ± 23.20) ng · h · ml ~ (-1), (112.97 ± 29.08) ng · h · ml ~ (-1) and (197.55 ± 68.51) ng · h · ml ~ (-1) respectively. Pharmacokinetic parameters of multi-dose group after oral administration of pitavastatin 2 mg: t 1/2 (13.07 ± 2.16) h, t. . Was (68.21 ± 20.82) ng · h · ml ~ (AUC, 0.48 ± 0.12) h, C (33.88 ± 6.91) ng · ml ~ · H · ml ~, AUC (0 ..) was (82.59 ± 26.58) ng · h · ml ~. After multiple doses of pitavastatin reached its steady state, the pharmacokinetic parameters t ~, t1 / 2 were consistent with those of single administration. CONCLUSION: AUC (. 8), AUC (吣) and C ~ of pitavastatin in the dose range of 1 ~ 4 mg have a linear relationship with the dose. Pitavastatin does not accumulate in vivo after multiple administrations There was no significant difference in the process of pitavastatin between men and women.