单次及多次口服奥美沙坦酯在中国健康受试者体内药代动力学研究

2014-09-26 10:20李坤艳等
中国当代医药 2014年22期

李坤艳等

[摘要] 目的 分析中国健康受试者单剂量或多次口服奥美沙坦酯后体内药代动力学的特征。 方法 单剂量实验:12名筛选合格的受试者,采用开放、随机、单剂量、三周期、3×3拉丁方设计方法将试验分为3组,每组4名,每周期分别服用相对应剂量的药物,且每周期服药前经过7 d的洗脱期。多次给药试验:12名健康受试者每天服用20 mg奥美沙坦酯,连续4 d。采集服药前0 h及服药后48 h内的血样,分析体内药物各PK参数。 结果 单剂量服用奥美沙坦

[关键词] 奥美沙坦酯;药代动力学;中国人

[中图分类号] R969.1 [文献标识码] A [文章编号] 1674-4721(2014)08(a)-0013-04

Pharmacokinetic study of olmesartan medoxomil in healthy Chinese subjects after single and multiple administrations

LI Kun-yan QIU Yu JIANG Yun LUO Cheng-hui YANG Nong LIN Xiao-ping ZHOU Chun-hua WANG Jing

GCP Center,Hunan Cancer Hospital;the Affiliated Cancer Hospital of Xiangya School of Medicine,Central South University,Changsha 410006,China

[Abstract] Objective To investigate pharmacokinetic characters of olmesartan medoxomil in healthy Chinese subjects after single and multiple administrations. Methods A single dose experiment:12 screening qualified subjects,the test wass divided into three groups by randomized-sequence,single-dose,3-treatment,3-period crossover design,each group of 4 peoples,each cycle respectively corresponding to the dose of drugs,and each cycle after 7 d washout period before taking the medicine.Multiple dosing test:12 healthy subjects were given 20 mg olmesartan medoxomil every day,continuous 4 d.Collected 0 h before taking the medicine and medication after blood analysis within 48 h of drugs in vivo PK parameters. Results Single dose olmesartan medoxomil (20,40,80 mg) after the maximum concentration in plasma (Cmax) were respectively (1016±349),(1503±266),(2516±1196) ng/ml,1/2 level elimination half-life (t1/2) for (5.2±1.2),(5.6±1.6),(6.2±0.9) h,after multiple dose olmesartan medoxomil,the Cmax and t1/2 was (894±301) ng/ml,(6.4±1.2) h respectively,single dose and t1/2 level differences between multiple dosing has no statistical significance.A single dose experiment,when within 20 to 80 mg dose,AUC0-∞,AUC0-48 and Cmax PK parameters with a linear relationship between dose of drug. Conclusion Olmesartan medoxomil has no accumulation in healthy Chinese subjects after 20 mg multiple-dose.

[Key words] Olmesartan medoxomil;Pharmacokinetics;Chinese

奥美沙坦酯是一个新型血管紧张素Ⅱ受体拮抗剂类抗高血压前药,临床显示有较好的安全性和有效性。体外以前体药物奥美沙坦酯形式存在,进入体内后通过肠壁、门静脉、肝脏等部位芳基酯酶脱酯作用转化成有药理活性的化合物奥美沙坦而发挥药理作用[1-3]。美国、欧洲、日本等国家已经对奥美沙坦体内药代动力学特征进行了较多的研究[4-11],研究结果显示,奥美沙坦在西方人和日本人体内的药代动力学特征没有种族差异性,但检索国内关于奥美沙坦药代动力学研究时,发现有相关研究显示,奥美沙坦在人体内的药动学特征具有一定的种族差异性[12-15]。研究数据显示,中国人服用单剂量奥美沙坦20 mg后,中国人体内的药物吸收速度和吸收程度均比西方人和日本人高,且消除速度也更快。这些发现对重新考虑奥美沙坦酯说明书关于中国人服用奥美沙坦的剂量与国外人群的剂量相同为每天20~40 mg的合理性提出质疑。但是目前没有更多相关研究证实上述这一结果,也没有关于中国人日服用>20 mg奥美沙坦时药代动力学的分析研究。本研究主要研究目的是验证在中国健康受试者体内服用20 mg奥美沙坦后的各药代动力学参数和分析在20~80 mg剂量范围内中国人体内奥美沙坦的药代动力学特征。

1 资料与方法

1.1 一般资料

12名健康中国受试者,男女各半,年龄20~25岁,体重51~60 kg,研究前均签订知情同意书。受试者均不吸烟,且无明显的临床疾病史,无心、肝、肾、消化道、神经系统、代谢系统以及精神异常等疾病,体格检查显示血压、心率、心电图、呼吸状况、肝肾功能、血常规、尿常规等均无有临床意义的异常;HIV、肝炎病毒B、C检测均为阴性;女性受试者妊娠检测为阴性。

1.2 试验设计

本研究阐述了在中国健康受试者体内单剂量或多次服用奥美沙坦酯的药代动力学特征,在剂量20~80 mg范围,奥美沙坦酯的药代动力学与剂量呈线性关系。多次服用奥美沙坦酯20 mg后,体内无蓄积作用。中国人体内奥美沙坦t1/2比西方人和日本人快2倍;相反,中国人体内奥美沙坦吸收比率比其高2倍。

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[14] 万茜,黄原原,付志敏,等.奥美沙坦氢氯噻嗪片在中国健康志愿者体中的药代动力学[J].中国临床药理学与治疗学,2011,16(4):393-399.

[15] 于洋,胡玉钦,刘建芳,等.单剂量口服奥美沙坦酯片在中国健康志愿者体内的药代动力学研究[J].解放军医药杂志,2014,26(1):67-69.

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[22] Rohatagi S,Carrothers TJ,Kshirsagar S,et al.Evaluation of population pharmacokinetics and exposure-response relationship with coadministration of amlodipine besylate and olmesartan medoxomil[J].J Clin Pharmacol,2008,48(7):823-836.

[23] Mizuno M,Sada T,Ikeda M,et al.Pharmacology of CS-866,a novel nonpeptide angiotensin Ⅱ receptor antagonist[J].Eur J Pharmacol,1995,285(2):181-188.

(收稿日期:2014-06-12 本文编辑:林利利)

[12] Jiang J,Liu D,Hu P.Pharmacokinetic and safety profile of olmesartan medoxomil in healthy Chinese subjects after single and multiple administrations[J].Pharmazie,2009, 64(5):323-326.

[13] Li KY,Liang JP,Hu BQ,et al.The relative bioavailability and fasting pharmacokinetics of three formulations of olmesartan medoxomil 20 mg capsules and tablets in healthy Chinese male volunteers:an open-label,randomized-sequence,single-dose,three-way crossover study[J].Clin Ther,2010,32(9):1674-1680.

[14] 万茜,黄原原,付志敏,等.奥美沙坦氢氯噻嗪片在中国健康志愿者体中的药代动力学[J].中国临床药理学与治疗学,2011,16(4):393-399.

[15] 于洋,胡玉钦,刘建芳,等.单剂量口服奥美沙坦酯片在中国健康志愿者体内的药代动力学研究[J].解放军医药杂志,2014,26(1):67-69.

[16] Tanaka H,Nagasawa Y,Matsui I,et al.Pharmacokinetics of olmesartan medoxomil in hemodialysis patients:little effect of dialysis upon its pharmacokinetics[J].Clin Exp Nephrol,2009,13(1):61-65.

[17] Rohatagi S,Lee J,Shenouda M,et al.Pharmacokinetics of amlodipine and olmesartan after administration of amlodipine besylate and olmesartan medoxomil in separate dosage forms and as a fixed-dose combination[J].J Clin Pharmacol,2008,48(11):1309-1322.

[18] Johnson JA.Predictability of the effects of race or ethnicity on pharmacokinetics of drugs[J].Int J Clin Phannacol Ther,2000,38(2):53-60.

[19] Gardner SF,Franks AM.Olmesartan medoxomil:the seventh angiotensin receptor antagonist[J].Ann Pharmacother,2003,37(1):99-105.

[20] Brousil JA,Burke JM.Olmesartan medoxomil:an angiotensin Ⅱ-receptor blocker[J].Clin Ther,2003,25(4):1041-1055.

[21] Nakagomi-Hagihara R,Nakai D,Kawai K,et al.OATP1B1,OATP1B3 and mrp2 are involved in hepatobiliary transport of olmesartan,a novel angiotensin Ⅱ blocker[J].Drug Metab Dispos,2006,34(5):862-869.

[22] Rohatagi S,Carrothers TJ,Kshirsagar S,et al.Evaluation of population pharmacokinetics and exposure-response relationship with coadministration of amlodipine besylate and olmesartan medoxomil[J].J Clin Pharmacol,2008,48(7):823-836.

[23] Mizuno M,Sada T,Ikeda M,et al.Pharmacology of CS-866,a novel nonpeptide angiotensin Ⅱ receptor antagonist[J].Eur J Pharmacol,1995,285(2):181-188.

(收稿日期:2014-06-12 本文编辑:林利利)

[12] Jiang J,Liu D,Hu P.Pharmacokinetic and safety profile of olmesartan medoxomil in healthy Chinese subjects after single and multiple administrations[J].Pharmazie,2009, 64(5):323-326.

[13] Li KY,Liang JP,Hu BQ,et al.The relative bioavailability and fasting pharmacokinetics of three formulations of olmesartan medoxomil 20 mg capsules and tablets in healthy Chinese male volunteers:an open-label,randomized-sequence,single-dose,three-way crossover study[J].Clin Ther,2010,32(9):1674-1680.

[14] 万茜,黄原原,付志敏,等.奥美沙坦氢氯噻嗪片在中国健康志愿者体中的药代动力学[J].中国临床药理学与治疗学,2011,16(4):393-399.

[15] 于洋,胡玉钦,刘建芳,等.单剂量口服奥美沙坦酯片在中国健康志愿者体内的药代动力学研究[J].解放军医药杂志,2014,26(1):67-69.

[16] Tanaka H,Nagasawa Y,Matsui I,et al.Pharmacokinetics of olmesartan medoxomil in hemodialysis patients:little effect of dialysis upon its pharmacokinetics[J].Clin Exp Nephrol,2009,13(1):61-65.

[17] Rohatagi S,Lee J,Shenouda M,et al.Pharmacokinetics of amlodipine and olmesartan after administration of amlodipine besylate and olmesartan medoxomil in separate dosage forms and as a fixed-dose combination[J].J Clin Pharmacol,2008,48(11):1309-1322.

[18] Johnson JA.Predictability of the effects of race or ethnicity on pharmacokinetics of drugs[J].Int J Clin Phannacol Ther,2000,38(2):53-60.

[19] Gardner SF,Franks AM.Olmesartan medoxomil:the seventh angiotensin receptor antagonist[J].Ann Pharmacother,2003,37(1):99-105.

[20] Brousil JA,Burke JM.Olmesartan medoxomil:an angiotensin Ⅱ-receptor blocker[J].Clin Ther,2003,25(4):1041-1055.

[21] Nakagomi-Hagihara R,Nakai D,Kawai K,et al.OATP1B1,OATP1B3 and mrp2 are involved in hepatobiliary transport of olmesartan,a novel angiotensin Ⅱ blocker[J].Drug Metab Dispos,2006,34(5):862-869.

[22] Rohatagi S,Carrothers TJ,Kshirsagar S,et al.Evaluation of population pharmacokinetics and exposure-response relationship with coadministration of amlodipine besylate and olmesartan medoxomil[J].J Clin Pharmacol,2008,48(7):823-836.

[23] Mizuno M,Sada T,Ikeda M,et al.Pharmacology of CS-866,a novel nonpeptide angiotensin Ⅱ receptor antagonist[J].Eur J Pharmacol,1995,285(2):181-188.

(收稿日期:2014-06-12 本文编辑:林利利)