title: Combined effects of itraconazole and CYP2D6*10 genetic polymorphism on the pharmacokinetics and pharmacodynamics of haloperidol in healthy subjects.
abstract: This study was to evaluate the combined effects of the CYP3A4 inhibitor itraconazole and the CYP2D6*10 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 CYP2D6*1/*1 and 10 for CYP2D6*10/*10). Four subjects (1 for CYP2D6*1/*1 and 3 for CYP2D6*10/*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 CYP2D6*10/*10 genotype showed 81% higher AUC compared to that of subjects with CYP2D6*1/*1 genotype (27.6 +/- 22.2 vs 50.2 +/- 47.1 ng h/mL). In the presence of itraconazole, subjects with CYP2D6*10/*10 showed 3-fold higher AUC of haloperidol compared to that of placebo pretreated subjects with CYP2D6*1/*1 genotype (21.7 +/- 11.3 vs 66.7 +/- 62.1 ng h/mL; P < 0.05). The CYP2D6*10 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 CYP2D6*10 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 CYP2D6*10/*10 in the presence of itraconazole pretreatment was significantly higher than that of subjects with CYP2D6*1/*1 genotype in the period of placebo pretreatment. Except for this, all other pharmacodynamic estimations did not reach to statistical significance although each CYP2D6*10 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.
authors.affiliation: Department of Pharmacology and Pharmacogenetics Research Center, Inje University College of Medicine, Busan, Korea.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Park
authors.forename: Ji-Hong
authors.initials: JH
authors.lastname: Shon
authors.forename: Kyoung-Ah
authors.initials: KA
authors.lastname: Kim
authors.forename: Hyun-Ju
authors.initials: HJ
authors.lastname: Jung
authors.forename: Joo-Cheol
authors.initials: JC
authors.lastname: Shim
authors.forename: Young-Ran
authors.initials: YR
authors.lastname: Yoon
authors.forename: In-June
authors.initials: IJ
authors.lastname: Cha
authors.forename: Jae-Gook
authors.initials: JG
authors.lastname: Shin
mesh_terms: D000328:Adult; D017109:Akathisia, Drug-Induced / Q000209:etiology; D000935:Antifungal Agents / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006220:Haloperidol / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology*; D007723:Korea; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008133:Long QT Syndrome / Q000209:etiology; D008297:Male; D011110:Polymorphism, Genetic
chemical_list: D000935:Antifungal Agents; D014150:Antipsychotic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D017964:Itraconazole; D003577:Cytochrome P-450 Enzyme System; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D006220:Haloperidol