Rätz A E, Schlienger R G, Linder L, Langewitz W, Haefeli W E
Department of Internal Medicine, University Hospital, Basel, Switzerland.
Clin Ther. 1999 May;21(5):829-40. doi: 10.1016/s0149-2918(99)80005-8.
Clomethiazole, a sedative-hypnotic and anticonvulsant drug, has been successfully administered orally and intravenously, but in cases where either of these methods presents complications, rectal administration may represent a practical alternative. We sought to compare the single-dose pharmacokinetics and pharmacodynamics of clomethiazole after oral and rectal administration. Ten healthy adult volunteers were given 600 mg clomethiazole edisylate (corresponding to 390 mg clomethiazole base) in 2 capsules as a single oral or rectal dose in a double-masked, double-dummy, crossover fashion. Serum concentrations were measured up to 10 hours after administration using a specific high-performance liquid chromatography method. Computerized reaction-time measurement and visual analogue scales (VAS) were used to assess drug effects. Peak serum concentrations were significantly higher after oral administration (mean +/- SEM, oral 1.76 +/- 0.47 microg/mL vs rectal 0.48 +/- 0.14 microg/mL; P = 0.03) and appeared earlier (55 +/- 12 vs 89 +/- 11 min; P = 0.04). Area under the concentration-time curve values were similar after administration by both routes (oral 116 +/- 20.6 vs rectal 105 +/- 36.0 microg x min/mL), with a relative rectal bioavailability of 90% compared with oral administration. The objective pharmacodynamic effects on reaction time (increase of 104 +/- 26 vs 66 +/- 22 ms, oral vs rectal) and working speed (decrease of 132 +/- 38 vs 97 +/- 32 ms, oral vs rectal) were not significantly different. Subjective pharmacodynamic effects, as measured on the VAS, were comparable with both routes of administration. Clomethiazole was well tolerated, with a similar adverse effect profile for both routes of administration. The effects of rectal dosing of clomethiazole were similar to those of oral dosing but appeared to occur later. Our results suggest that rectal administration of a single 600-mg clomethiazole edisylate dose bears no safety risk. Therefore, rectal administration could be considered when neither oral nor parenteral administration is possible and a later onset of effect is not critical.
氯美噻唑是一种镇静催眠和抗惊厥药物，已成功通过口服和静脉给药，但在这些方法出现并发症的情况下，直肠给药可能是一种可行的替代方法。我们试图比较氯美噻唑口服和直肠给药后的单剂量药代动力学和药效学。10名健康成年志愿者以双盲、双模拟、交叉方式，口服或直肠单剂量给予2粒胶囊中的600mg氯美噻唑乙磺酸盐（相当于390mg氯美噻唑碱）。给药后长达10小时使用特定的高效液相色谱法测量血清浓度。使用计算机化反应时间测量和视觉模拟量表（VAS）评估药物效果。口服给药后血清峰值浓度显著更高（平均值±标准误，口服1.76±0.47μg/mL，直肠0.48±0.14μg/mL；P = 0.03），且出现更早（55±12分钟对89±11分钟；P = 0.04）。两种给药途径给药后的浓度-时间曲线下面积值相似（口服116±20.6对直肠105±36.0μg·分钟/mL），与口服给药相比，直肠相对生物利用度为90%。对反应时间（口服增加104±26毫秒对直肠增加66±22毫秒）和工作速度（口服降低132±38毫秒对直肠降低97±32毫秒）的客观药效学作用无显著差异。通过VAS测量的主观药效学作用在两种给药途径中相当。氯美噻唑耐受性良好，两种给药途径的不良反应谱相似。氯美噻唑直肠给药的效果与口服给药相似，但似乎起效较晚。我们的结果表明，直肠给予单剂量600mg氯美噻唑乙磺酸盐无安全风险。因此，当无法进行口服或胃肠外给药且起效延迟不重要时，可考虑直肠给药。
