Dahl M L, Ekqvist B, Widén J, Bertilsson L
Department of Clinical Pharmacology, Karolinska Institute, Huddinge University Hospital, Sweden.
Acta Psychiatr Scand. 1991 Jul;84(1):99-102. doi: 10.1111/j.1600-0447.1991.tb01428.x.
The pharmacokinetics of a single oral dose of the neuroleptic drug zuclopenthixol (10 or 6 mg) was studied in 6 extensive and 6 poor metabolizers of debrisoquine. The peak plasma concentrations of zuclopenthixol did not differ between the phenotypes, whereas the plasma elimination half-life was significantly longer in poor than in extensive metabolizers (29.9 +/- 6.6 vs 17.6 +/- 6.9 h). Accordingly, the total oral plasma clearance was lower in poor than in extensive metabolizers (0.78 +/- 0.27 vs 2.12 +/- 0.65 1/h/kg). Ten of the volunteers had previously participated in a similar study in which the kinetics of perphenazine, another neuroleptic drug, were studied in poor and in extensive metabolizers of debrisoquine. There was a significant correlation between the oral clearance of perphenazine and that of zuclopenthixol among these 10 subjects. The study indicates that the disposition of zuclopenthixol, as well as that of perphenazine, is related to the genetically determined capacity to hydroxylate debrisoquine. The significance of this polymorphism for the clinical use of neuroleptics is discussed.
对6名异喹胍强代谢者和6名异喹胍弱代谢者，研究了单剂量口服抗精神病药物珠氯噻醇（10或6毫克）的药代动力学。珠氯噻醇的血浆峰浓度在不同表型之间无差异，而弱代谢者的血浆消除半衰期显著长于强代谢者（29.9±6.6对17.6±6.9小时）。因此，弱代谢者的口服血浆总清除率低于强代谢者（0.78±0.27对2.12±0.65升/小时/千克）。其中10名志愿者之前参加过一项类似研究，在该研究中对另一种抗精神病药物奋乃静在异喹胍弱代谢者和强代谢者中的药代动力学进行了研究。在这10名受试者中，奋乃静的口服清除率与珠氯噻醇的口服清除率之间存在显著相关性。该研究表明，珠氯噻醇以及奋乃静的处置与异喹胍羟基化的遗传决定能力有关。讨论了这种多态性对抗精神病药物临床应用的意义。
