Roh H K, Chung J Y, Oh D Y, Park C S, Svensson J O, Dahl M L, Bertilsson L
Department of Medical Laboratory Sciences and Technology, Division of Clinical Pharmacology, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden.
Br J Clin Pharmacol. 2001 Sep;52(3):265-71. doi: 10.1046/j.0306-5251.2001.01437.x.
This study was carried out to evaluate the influence of CYP2D6 genotype on the steady state plasma concentrations of haloperidol and reduced haloperidol in Korean schizophrenic patients.
One hundred and twenty Korean schizophrenic patients treated with various, clinically determined, doses of haloperidol (range 3-60, median 20 mg day-1) during monotherapy were recruited. CYP2D6 genotypes were determined by analysis of the CYP2D610 allele using allele-specific PCR and the CYP2D65 allele by long-PCR. Steady state plasma concentrations of haloperidol and reduced haloperidol were analysed by h.p.l.c.
Twenty-three (19.2%), 60 (50.0%), 1 (0.8%), 33 (27.5%) and 3 patients (2.5%) possessed the CYP2D6 genotypes *1/*1, *1/*10, *1/*5, *10/*10 and *10/5, respectively. The allele frequencies of CYP2D61, *10 and 5 were 44.6%, 53.8% and 1.7%, respectively. Significant relationships between dose and plasma concentrations of haloperidol (linear; r2 = 0.60, P < 0.0001) and reduced haloperidol (quadratic equation; r(2) = 0.67) were observed. Overall, the concentrations normalized for dose (C/D) of haloperidol were significantly different between the CYP2D61/*1, *1/*10 and *10/*10 genotype groups (one-way ANOVA; P = 0.028). No significant differences between the genotype groups were found with respect to the C/D of reduced haloperidol (P = 0.755). However, in patients with daily doses less than 20 mg, significant differences in the C/D of haloperidol (P = 0.003), but not of reduced haloperidol, were found between the three major genotype groups. In patients with doses higher than 20 mg, no differences were found between the genotype groups for either haloperidol or reduced haloperidol. 68 patients (57%) used benztropine, an antimuscarinic agent. All four patients with a *5 allele (one together with *1 and three with *10) were found to use benztropine. The patients homozygous for the *1 allele seemed to need less benztropine than the patients with one or two mutated alleles (Fisher's exact test; P = 0.036).
The dose-corrected steady state plasma concentrations of haloperidol, but not of reduced haloperidol, were significantly different between the CYP2D6*1/*1, *1/*10 and *10/*10 genotype groups when doses lower than 20 mg haloperidol were given. No differences were found at higher doses. These results suggest the involvement of CYP2D6 in the metabolism of haloperidol at low doses of haloperidol (< 20 mg daily), while another enzyme, probably CYP3A4, contributes at higher doses.
本研究旨在评估CYP2D6基因多态性对韩国精神分裂症患者中氟哌啶醇及还原氟哌啶醇稳态血药浓度的影响。
招募120例接受不同临床剂量氟哌啶醇（范围3 - 60mg，中位数20mg/天）单药治疗的韩国精神分裂症患者。采用等位基因特异性PCR分析CYP2D610等位基因，长PCR分析CYP2D65等位基因，从而确定CYP2D6基因型。采用高效液相色谱法分析氟哌啶醇及还原氟哌啶醇的稳态血药浓度。
分别有23例（19.2%）、60例（50.0%）、1例（0.8%）、33例（27.5%）和3例（2.5%）患者的CYP2D6基因型为*1/*1、*1/*10、*1/*5、10/10和10/5。CYP2D61、10和5的等位基因频率分别为44.6%、53.8%和1.7%。观察到氟哌啶醇剂量与血药浓度之间存在显著的线性关系（r2 = 0.60，P < 0.0001），还原氟哌啶醇剂量与血药浓度之间存在显著的二次方程关系（r(2) = 0.67）。总体而言，氟哌啶醇剂量校正血药浓度（C/D）在CYP2D61/1、1/10和10/10基因型组间存在显著差异（单因素方差分析；P = 0.028）。还原氟哌啶醇的C/D在基因型组间未发现显著差异（P = 0.755）。然而，在日剂量低于20mg的患者中，三个主要基因型组间氟哌啶醇的C/D存在显著差异（P = 0.003），而还原氟哌啶醇的C/D无显著差异。在日剂量高于20mg的患者中，氟哌啶醇及还原氟哌啶醇的基因型组间均未发现差异。68例患者（57%）使用了抗胆碱能药物苯海索。所有4例携带5等位基因的患者（1例与1等位基因同时存在，3例与10等位基因同时存在）均使用了苯海索。*1等位基因纯合的患者似乎比携带一个或两个突变等位基因的患者需要更少的苯海索（Fisher精确检验；P = 0.036）。
当给予氟哌啶醇剂量低于20mg时，CYP2D6*1/*1、*1/10和10/*10基因型组间氟哌啶醇的剂量校正稳态血药浓度存在显著差异，而还原氟哌啶醇无显著差异。高剂量时未发现差异。这些结果表明，低剂量（<20mg/天）氟哌啶醇代谢中CYP2D6起作用，而高剂量时可能是另一种酶（可能是CYP3A4）起作用。
