摘要
目的：1建立测定西沙必利血药浓度的高效液相色谱荧光检测法，研
究国产西沙必利胶囊在中国健康志愿者体内的药代动力学特征及相对生物
利用度。2探讨在联合用药情况下，奥美拉唑对西沙必利在兔体内药代动
力学特征的影响。从而为西沙必利临床合理应用提供实验依据。方法：采
用双周期交叉试验设计，12名健康志愿者随机分成两组，分别口服国产
西沙必利片剂和胶囊15mg，一周后交叉。用高效液相色谱荧光检测法测
定不同时间点血浆中西沙必利浓度，用3P97软件拟合房室模型，计算药
代动力学参数并进行生物等效性评价。用高效液相色谱荧光检测法检测单
独应用西沙必利及联合用药用药情况下（与奥美拉唑合用）的西沙必利血
药浓度，用3P97软件拟合房室模型，计算药代动力学参数。结果：国产
西沙必利胶囊和片剂的血药浓度-时间曲线符合二房室开放模型，其主要
药代动力学参数：C_(max)分别为79.87±11.26和75.24±12.85μg/L，T_(max)分别
为1.50±0.21和1.54±0.33h，AUC_(0-36)分别为777.05±128.47和771.61±129.01
μg/L·h，T_((1/2)β)分别为10.07+0.81和9.79+1.27h。国产西沙必利胶囊的相
对生物利用度为101.12+9.89％。经方差分析和双单侧t检验，两制剂生物
等效。兔单独用药组与联合用药组主要药代动力学参数：C_(max)分别为
26.21±6.77和28.32±3.79μg/L，AUC_(0-24)分别为217.61+48.25和247.91+31.26
μg/L·h，T_((1/2)β)分别为8.30±0.67和8.81±0.50h，T_(max)均为0.92±0.17h。经
t险验无显著性差异。结论：西沙必利血药浓度的高效液相色谱荧光检测
法准确，灵敏，可靠。国产西沙必利胶囊与片剂生物等效。奥美拉唑对单
次口服治疗量西沙必利在兔体内的药代动力学过程无显著性改变。
Objective: 1. A HPLC-FLUOR method with detection was developed and validated to
de ermine cisapride in plasma, to study the pharmacokinetics profile and bioequivalence of
cispride in Chinese healthy volunteers. 2. To study the pharmacokinetics profiles of cisapride
co ribined with omeprazole in rabbits. Methods: The study was conducted in a two-way
cross-over design, as a single does randomized trial. Each volunteer was orally given
cisapride tablet and capsule. Eight rabbits were divided into cispride group and in
co ribination with omeprazole group. Plasma samples were assayed for cisapride using high-
pe formance liquid chromatography method with fluorescence detection. The
ph irmacokinetics pharmeters as well as relative bioavailability were measured. To compare
the difference of two groups and realize the case of drugs interaction under the condition of
co nbination with omeprazo]e. Results: the concentration-time curves of two formulations
were conformed to a two-compartment open model with first-order absorption. The main
phirmacokinetic pharmeters of capsule or tablet were as follows: ~ were 79.87?1.26 and
75.24?2.85 it gIL; Tmax were 1.50+0.21 and 1.54?.33 h; AUC036 were 777.05?28.47 and
77 1.61?29.01 it gIL h; T112~ were 10.07?.81 and 9.79?.27 h respectively. There were
no significant difference between the two formulations (P>0.05). The relative bioavailability
of cisapride capsule was 101.12?.89%. The pharmacokinetics parameters of single-does
group and combination-does group of rabbits were as follow: ~ were 26.21?.77 and
28.32?.79 It g/L; AUC024 were 217.61+48.25 and 247.91?1.26 It gIL h; T112~ were
8.20+0.67 and 8.8 1?.50 h respectively; Tiiia~ were all 0.92?.17 h. There were no significant
different between these parameters. Conclusion: A HPLC-FLUOR method that determine
cuapride in plasma is sensitive, accurate and reliable. Domestic cisapride capsule and tablet
were bioequivalent. The pharmacokinetics profiles of single-does cisapride will not be
chtnged by co-administered omeprazole.
引文
1 屈桂秋．胃复安的副作用及应用注意事项，药学通报，1985；70(1)：61
2 姚光弼．消化道动力障碍和促动力药．中华消化杂志，1992；12(2)：63～64
3 McCallum RW, Prankash C, Campoli-Richards DM et al. Cisapride a preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic use as a prokinetic agent in gastrointestinal motility disorders. Drugs, 1988; 36:652～681
4 Farrington E. Cardiac toxicty with cisapride. Pediatr Nurs, 1996; 22(3): 256
5 段京莉，严宝霞．西沙必利不良反应的再评价．中国药学杂志，2000；35(12)：851～854
6 Y.Preechagvon, B. G. Chahes. Andysis of cisapride in neonatal plasma using high-performance liquid chromatography with a basestable column and fluorescence detection. Journal of Chromatography B, 1995; 670:139～143
7 R.Wvestenborghs, W. Lorreyne, F. Van Roimpaey and J. Heykants. Determination of cisapride in plasma and animal tissue by high-performance liquid chromatography. Journal of Chromatography B,1988; 424:195～200
8 Michiels M, Monbaliu J, Hendriks R et al. Pharmacokinetics and tissue distribution of the new gastrokinetic agent cisapride in rat, rabbit and dog. Drug research, 1987; 37:1159～1167
9 H.Bohets, K Lavijsen, J. van Houdt et al. Identification of the cytochrome P450 enzymes involved in the metabolism of cisapride: in vitro studies of potential co-medication interactions. British Journal of Pharmacology, 2000; 129:1655～1667
10 Meuldermans W, Van Peer A, Heddrickx JR et al. Excretion and biotransformation of cisapride in dogs and humans after oral admiistration. Drug metab dispos, 1988; May-Jun 16(3): 403～409
11 Timothy A Bedford and David J. Rowbotham. Cisapride drug interaction of clinical significance. Drug Safety, 1996; 15(3): 167～175
12 Tonini M, De-Ponti F, Di-Nucci A, et al. Review article, cardiac adverse effects of gastrointestinal prokinetics. Aliment Pharmacol Ther, 1999; 13(12): 1585
13 Yamamoto T, Tabkano K, Sanaka M, et al. Pharmacokinetic characteristics of cisapride in elderly patients. Int J Chin Pharmacol Ther, 1998; 36(8): 432～434
14 邵润轩，郭宏华，周长玉等．奥美拉唑、西沙必利联合治疗反流性食管炎．综合临床医学，1998；14(1)：80～81
15 陈永宁．奥美拉唑联合西沙必利治疗反流性食管炎．中国新药与临床杂志，1998；17(3)：187～188
16 Kimming JM. Treatment and prevention of relapse of mild vesophagitis with omeprazole and cisapride comparison of two strategies. Aliment Pharmacol Ther, 1995; 9(3): 281～286
17 Zomorodi K, Howston TB. Selectivity of omeprazole inhibition towards rat liver cytochromes P450. Xenobiotica, 1997; 27(1): 49～58
18 Furuta S, Kamada E, Suzuki T, et al. Inhibition of drug metabolism in human liver microsomes by nizatidine cimetidine and omeprazole. Xenobiotica, 2001; 31(1): 1～10