Park Ji-Young, Shon Ji-Hong, Kim Kyoung-Ah, Jung Hyun-Ju, Shim Joo-Cheol, Yoon Young-Ran, Cha In-June, Shin Jae-Gook
Department of Pharmacology and Pharmacogenetics Research Center, Inje University College of Medicine, Busan, Korea.
J Clin Psychopharmacol. 2006 Apr;26(2):135-42. doi: 10.1097/01.jcp.0000203199.88581.c3.
This study was to evaluate the combined effects of the CYP3A4 inhibitor itraconazole and the CYP2D610 genotype on the pharmacokinetics and pharmacodynamics of haloperidol, a substrate of both CYP2D6 and CYP3A4, in healthy subjects. Nineteen healthy volunteers whose CYP2D6 genotypes were predetermined were enrolled (9 for CYP2D61/1 and 10 for CYP2D610/10). Four subjects (1 for CYP2D61/1 and 3 for CYP2D610/10) did not complete the study because of adverse events. The pharmacokinetics of haloperidol and its pharmacodynamic effects measured for QTc prolongation and neurologic side effects were evaluated after a single dose of 5 mg haloperidol following a pretreatment of placebo or itraconazole at 200 mg/d for 10 days in a randomized crossover manner. Itraconazole pretreatment increased the mean area under the time-concentration curves (AUCs) of haloperidol by 55% compared to placebo pretreatment (21.7 +/- 11.3 vs 33.5 +/- 29.3 ng h/mL). The subjects with CYP2D610/10 genotype showed 81% higher AUC compared to that of subjects with CYP2D61/1 genotype (27.6 +/- 22.2 vs 50.2 +/- 47.1 ng h/mL). In the presence of itraconazole, subjects with CYP2D610/10 showed 3-fold higher AUC of haloperidol compared to that of placebo pretreated subjects with CYP2D61/1 genotype (21.7 +/- 11.3 vs 66.7 +/- 62.1 ng h/mL; P < 0.05). The CYP2D610 genotype and itraconazole pretreatment decreased the oral clearance of haloperidol by 24% and 25%, respectively, but without a statistical significance. In the subjects with both CYP2D610 genotype and itraconazole pretreatment, however, the oral clearance was significantly decreased to 42% of subjects with wild genotype in the placebo pretreatment (4.7 +/- 3.6 vs 2.0 +/- 1.9 L/h/kg; P < 0.05). Barnes Akathisia Rating Scale (BARS) of subjects with CYP2D610/10 in the presence of itraconazole pretreatment was significantly higher than that of subjects with CYP2D61/1 genotype in the period of placebo pretreatment. Except for this, all other pharmacodynamic estimations did not reach to statistical significance although each CYP2D610 genotype and itraconazole pretreatment caused higher value of UKU side effect and BARS scores. The moderate effect of CYP2D6*10 genotype on the pharmacokinetics and pharmacodynamics of haloperidol seems to be augmented by the presence of itraconazole pretreatment.
本研究旨在评估CYP3A4抑制剂伊曲康唑与CYP2D610基因型对健康受试者中同时作为CYP2D6和CYP3A4底物的氟哌啶醇的药代动力学和药效学的联合影响。纳入了19名预先确定CYP2D6基因型的健康志愿者（9名CYP2D61/1型和10名CYP2D610/10型）。4名受试者（1名CYP2D61/1型和3名CYP2D610/10型）因不良事件未完成研究。在以随机交叉方式给予安慰剂或200mg/d伊曲康唑预处理10天后，单次给予5mg氟哌啶醇，评估氟哌啶醇的药代动力学及其针对QTc延长和神经副作用所测量的药效学效应。与安慰剂预处理相比，伊曲康唑预处理使氟哌啶醇的平均时间-浓度曲线下面积（AUC）增加了55%（21.7±11.3 vs 33.5±29.3 ng·h/mL）。CYP2D61/1基因型受试者的AUC比CYP2D610/10基因型受试者低81%（27.6±22.2 vs 50.2±47.1 ng·h/mL）。在伊曲康唑存在的情况下，CYP2D610/10基因型受试者的氟哌啶醇AUC比安慰剂预处理的CYP2D61/1基因型受试者高3倍（21.7±11.3 vs 66.7±62.1 ng·h/mL；P<0.05）。CYP2D610基因型和伊曲康唑预处理分别使氟哌啶醇的口服清除率降低了24%和25%，但无统计学意义。然而，在同时具有CYP2D610基因型和伊曲康唑预处理的受试者中，口服清除率显著降至安慰剂预处理的野生基因型受试者的42%（4.7±3.6 vs 2.0±1.9 L/h/kg；P<0.05）。伊曲康唑预处理存在时，CYP2D610/10基因型受试者的巴恩斯静坐不能评定量表（BARS）显著高于安慰剂预处理期的CYP2D61/1基因型受试者。除此之外，尽管每种CYP2D6基因型和伊曲康唑预处理均导致UKU副作用和BARS评分较高，但所有其他药效学评估均未达到统计学意义。伊曲康唑预处理的存在似乎增强了CYP2D6*10基因型对氟哌啶醇药代动力学和药效学的中度影响。
