Effect of CYP2D6 Genotypes on the Metabolism of Haloperidol in a Japanese Psychiatric Population

Abstract

We investigated the effect of CYP2D6 genotypes on plasma levels of haloperidol (HAL) and reduced haloperidol (RHAL) in 88 Japanese schizophrenic inpatients being treated with HAL. Some subjects carrying CYP2D6*5 allele (CYP2D6*1/CYP2D6*5, CYP2D6*5/ CYP2D6*10) showed extremely high concentrations of both HAL and RHAL, and the groups with CYP2D6*5 allele seemed to have higher plasma concentrations of HAL (1.14 7 0.69 ng/ml/mg) and RHAL (1.10 7 1.05 ng/ml/mg) than the other groups. Among those without CYP2D6*5 allele, there were no significant differences in plasma concentrations of HAL and RHAL between those without CYP2D6*10 allele (HAL ¼ 0.68 7 0.31 ng/ml/mg, RHAL ¼ 0.28 7 0.37 ng/ml/mg), those with one CYP2D6*10 (HAL ¼ 0.70 7 0.23 ng/ ml/mg, RHAL ¼ 0.31 7 0.16 ng/ml/mg) and those with two CYP2D6*10 alleles (HAL ¼ 0.69 7 0.14 ng/ml/mg, RHAL ¼ 0.40 7 0.09 ng/ ml/mg), although there was a tendency of higher plasma concentration of RHAL in those with two CYP2D6*10 alleles. At a lower daily dosage of HAL (o10 mg/day), the subjects with two or one CYP2D6*10 allele(s) showed significantly higher plasma concentrations of RHAL (0.43 7 0.23 ng/ml/mg, 0.34 7 0.16 ng/ml/mg) than those without CYP2D6*10 allele (0.18 7 0.16 ng/ml/mg). The results of this study indicate that CYP2D6*10 allele plays significant but modest role in HAL metabolism in Japanese; nevertheless, we should not lump CYP2D6*10 allele with CYP2D6*5 allele because these two mutated alleles seem to have different impacts in the metabolism of HAL.

Effects of DRD2 and CYP2D6 genotypes on delta EEG power response to aripiprazole in healthy male volunteers: a preliminary study

“…However, Table 4 and Figure 4 showed that subjects with the à 1/ à 10 genotype exhibited a trend toward higher AUC values after the administration of aripiprazole. The à 10 allele, which induces reduction of enzyme affinity for the substrate, has been associated with the high plasma levels and AUC values after the administration of several psychoactive drugs, including haloperidol, nortriptyline, paroxetine and aripiprazole (Yoon et al, 2000;Dalen et al, 2003;Someya et al, 2003;Kubo et al, 2005). Our findings are in accordance with the previous studies, except that subjects with the à 10/ à 10 genotype exhibited lower AUC values than did the subjects with the à 1/ à 10 genotypes (Figure 4).…”

Polymorphisms in the 5-Hydroxytryptamine 2A Receptor and CytochromeP4502D6 Genes Synergistically Predict Fluvoxamine-Induced Side Effects in Japanese Depressed Patients

“…In the former study, the patients were divided into three genotype groups by the number of CYP2D6 mutated alleles: *1/*1, *1/*5 or *1/*10, and *5/*10 or *10/*10, whereas, in this study, the patients were divided into two genotype groups by the degree of enzyme activity: *1/*1 or *1/*10 and *10/*10, *1/*5 or *5/*10. We previously reported that one *5 allele had a greater impact on the metabolism of haloperidol, a substrate of CYP2D6, than one *10 allele (Someya et al, 2003). Since *1/*10 has only one mutation causing decreased enzyme activity, it was supposed that the enzyme activity of *1/*10 was almost equal to that of the *1/*1 genotype in this study.…”

Cytochrome P-450 2D6*10 C188T Polymorphism Is Associated with Antipsychotic-Induced Persistent Tardive Dyskinesia in Chinese Schizophrenic Patients

“…A recent study investigated the effect of CYP2D6 genotypes on the plasma level of HAL and RHAL in 88 Japanese schizophrenic patients. They found that patients carrying the CYP2D6*5 allele seemed to have a higher plasma level of both HAL and RHAL regardless of carrying the CYP2D6*10 allele or not [29]. Therefore, other genetic analyses for the association between the CYP2D6 gene and TD in the Chinese ethnic subjects deserve attention before drawing any conclusion regarding the role of the CYP2D6 gene on the susceptibility to TD.…”