性别因素对替利定及其代谢物去甲替利定在中国健康志愿者中药代动力学的影响

doi:10.5246/jcps.2012.01.013

性别因素对替利定及其代谢物去甲替利定在中国健康志愿者中药代动力学的影响

孙莉, 李潇潇, 范华莹, 梁军成, 邓艳萍^*

北京大学中国药物依赖性研究所, 北京 100191

收稿日期:2011-05-10 修回日期:2011-09-10 出版日期:2012-01-01 发布日期:2012-01-01
通讯作者: 邓艳萍*

Influence of sex differences on the pharmacokinetics of tilidine and its metabolites nortilidine in healthy Chinese volunteers

Li Sun , Xiao-Xiao Li , Hua-Ying Fan, Jun-Cheng Liang, Yan-Ping Deng^*

National Institute on Drug Dependence, Peking University, Beijing 100191, China

Received:2011-05-10 Revised:2011-09-10 Online:2012-01-01 Published:2012-01-01
Contact: Yan-Ping Deng*

摘要/Abstract

摘要： 比较替利定和它的代谢物去甲替利定在不同性别中国健康志愿者中的药代动力学特征。9例 (4例男性, 5例女性) 健康志愿者单次口服50 mg盐酸替利定口服液, 在规定时间内采血, 采用GC-NPD测定血药浓度, 用非房室模型计算药代动力学参数。替利定和代谢物去甲替利定的主要动力学参数分别为: Cmax (63.39±28.99) 和(122.53±23.23) ng/mL; Tmax (0.37±0.07) 和 (0.64±0.30) h; t1/2(2.83±1.35) 和 (5.72±1.37) h; AUC0-∞ (101.59±41.85) 和 (577.13±189.77) ng·h/mL。替利定的男性和女性药动学参数分别为: Cmax (73.88±40.88) 和 (55.01±15.16) ng/mL, Tmax (0.37±0.08) 和 (0.36±0.08) h, t1/2(4.05±1.07) 和 (1.86±0.41) h, AUC0-∞ (119.00±55.11) 和 (87.66±26.08) ng·h/mL。代谢物去甲替利定的男性和女性药动学参数分别为: Cmax (108.82±27.88)和(133.49±12.56) ng/mL, Tmax (0.94±0.13)和(0.40±0.09) h, t1/2(4.66±1.18) 和 (6.57±0.84) h, AUC0-∞ (601.59±281.07)和 (557.57±108.16) ng·h/mL。替利定的t1/2男性比女性长, 代谢物去甲替利定的Tmax男性比女性慢, 其它主要药代参数男性和女性之间没有统计学差异。受试者无严重不良事件发生, 男性和女性的不良事件发生率有显著性差异。药代动力学研究显示, 替利定口服液在应用于中国人时无需改变用药剂量, 且性别因素影响不大。

Abstract:

This study was conducted to assess the pharmacokinetic characteristics of tilidine and its active metabolites nortilidine in healthy Chinese male and female volunteers. Nine healthy volunteers (4 male and 5 female) were included in the study. Subjects were administered a single oral dose 50 mg tilidine hydrochloride oral solution. The plasma tilidine and nortilidine concentrations were determined by gas chromatography nitrogen phosphorous detection (GC-NPD). The pharmacokinetic parameters were estimated from plasma concentration-time profiles using model independent method. The main pharmacokinetic data (mean±SD) for tilidine and nortilidine were Cmax (63.39±28.99) and (122.53±23.23) ng/mL; Tmax (0.37±0.07) and (0.64±0.30) h; t1/2(2.83±1.35) and (5.72±1.37) h; AUC0-∞ (101.59±41.85) and (577.13±189.77) ng·h/mL, respectively. The mean pharmacokinetic parameters for male and female were as follows: for tilidine: Cmax (73.88±40.88) and (55.01±15.16) ng/mL, Tmax (0.37±0.08) and (0.36±0.08) h, t1/2(4.05±1.07) and (1.86±0.41) h, AUC0-∞ (119.00±55.11) and (87.66±26.08) ng·h/mL; for nortilidine: Cmax (108.82±27.88) and (133.49±12.56) ng/mL, Tmax (0.94±0.13) and (0.40±0.09) h, t1/2(4.66±1.18) and (6.57±0.84) h, AUC0-∞ (601.59±281.07) and (557.57±108.16) ng·h/mL. The t1/2 for tilidine in male was significantly higher than that in female, while Tmax for nortilidine in male was significantly higher than that in female. There was no serious adverse effects, but significant difference in the incidence of adverse effects was found between male and female. There was no sufficient pharmacokinetic reason to adjust the dose of tilidine when it was administered in Chinese patients.

中图分类号:

R969.1

Supporting:

Foundation item: Major Project of National Science & Technology (Grant No. 2009ZX09301-010).
^*Corresponding author. Tel.: 86-10-82801340

孙莉, 李潇潇, 范华莹, 梁军成, 邓艳萍^*. 性别因素对替利定及其代谢物去甲替利定在中国健康志愿者中药代动力学的影响[J]. , DOI: 10.5246/jcps.2012.01.013.

Li Sun , Xiao-Xiao Li , Hua-Ying Fan, Jun-Cheng Liang, Yan-Ping Deng^*. Influence of sex differences on the pharmacokinetics of tilidine and its metabolites nortilidine in healthy Chinese volunteers [J]. , DOI: 10.5246/jcps.2012.01.013.

参考文献

[1] Hajda, J.P.; Jähnchen, E.; Oie, S.; Trenk, D. J. Clin. Pharmacol. 2002, 42, 1257-1261.
[2] Seiler, K.U.; Jähnchen, E.; Trenk, D.; Brennscheidt, U.; Heintz, B. J. Clin. Pharmacol. 2001, 41, 79-84.
[3] Regenthal, R.; Krüger, M.; Richter, M.; Preiss, R. Hum. Exp. Toxicol. 1998, 17, 593-597.
[4] Brennscheidt, U.; Seiler, K.U.; Thomann, P. Arzneimittelforschung. 2000, 50, 1015-1022.
[5] Dubinsky, B.; Crew, M.C.; Melgar, M.D.; Karpowicz, J.K.; Di Carlo, F.J. Biochem. Pharmacol. 1975, 24, 277-281.
[6] Schulz, R.; Bläsig, J.; Wüster, M.; Herz, A. Naunyn Schmiedebergs Arch. Pharmacol. 1978, 304, 89-93.
[7] Thierry, C.; Boeynaems, J.M.; Paolo, M. Eur. J. Pharmacol. 2005, 506, 205-208.
[8] Weiss, J.; Sawa, E.; Riedel, K.D.; Haefeli, W.E.; Mikus, G. Naunyn Schmiedebergs Arch. Pharmacol. 2008, 378, 275-282.
[9] Xie, H.G.; Kim, R.B.; Wood, A.J.; Stein, C.M. Annu. Rev. Pharmacol. Toxicol. 2001, 41, 815-850.
[10] Xie, H.G.; Stein, C.M.; Kim, R.B.; Wilkinson, G.R.; Flockhart, D.A.; Wood, A.J. Pharmacogenetics. 1999, 9, 539-549.
[11] Hunt, C.M.; Westerkam, W.R.; Stave, G.M. Biochem. Pharmacol. 1992, 44, 275-283.
[12] Hooper, W.D.; Qing, M.S. Clin. Pharmacol. Ther. 1990, 48, 633-640.
[13] Roth, M.E.; Cosgrove, K.P.; Carroll, M.E. Neurosci. Biobehav. Rev. 2004, 28, 533-546.
[14] Hengy, H.; Vollmer, K.O.; Gladigau, V. J. Pharm. Sci. 1978, 67, 1765-1768.
[15] Cordonnier, J.; Wauters, A.; Heyndrickx, A. J. Anal. Toxicol. 1987, 11, 144-148.
[16] Martin, W.; Ring, J.; Gaupp, M.; Arnold, P.; Sennewald, R.; Doser, K. Arzneimittelforschung. 1999, 49, 599-607.
[17] Vollmer, K.O.; Thomann, P.; Hengy, H. Arzneimittelforschung. 1989, 39, 1283-1288.
[18] Westlind, A.; Löfberg, L.; Tindberg, N.; Andersson, T.B.; Ingelman-Sundberg, M. Biochem. Biophys. Res. Commun. 1999, 259, 201-205.
[19] Ozdemir, V.; Kalow, W.; Tang, B.K.; Paterson, A.D.; Walker, S.E.; Endrenyi, L.; Kashuba, A.D. Pharmacogenetics. 2000, 10, 373-388.