We investigated the effect of the CYP2C19 and CYP2D6 genotypes on the metabolism of amitriptyline (AT) in Japanese psychiatric patients. Steady-state concentrations of AT and its metabolites (nortriptyline [NT], trans-10-hydroxy-nortriptyline [EHNT], cis-10-hydroxy-nortriptyline [ZHNT], trans-10-hydroxy-amitriptyline [EHAT], and cis-10-hydroxy-amitriptyline [ZHAT]) in 50 patients were determined by high-performance liquid chromatography. Significantly higher plasma concentrations of AT corrected for dose and body weight in the subjects with two mutated alleles of CYP2C19 than in those with no mutated alleles of CYP2C19 were observed (no mutated alleles vs. two mutated alleles: 36.0 +/- 18.2 vs. 64.0 +/- 25.2 ng/mL/mg/kg, p = 0.025). A significantly higher AT/NT ratio was seen in the subjects with two mutated alleles of CYP2C19 than in those with no mutated alleles of CYP2C19 (no mutated alleles vs. two mutated alleles: 1.27 +/- 0.59 vs. 3.40 +/- 1.02, p = 0.001). A trend for higher NT/EHNT ratio in the subjects with two mutated alleles of CYP2D6 than in those with no mutated alleles of CYP2D6 was observed (no mutated alleles vs. two mutated alleles: 0.73 +/- 0.39 vs. 1.31 +/- 0.81, p = 0.068). A trend for higher plasma concentrations of total hydroxylated metabolites of AT (EHAT + ZHAT) corrected for dose and body weight in the subjects with two mutated alleles of CYP2C19 than in those with no mutated alleles of CYP2C19 was found (no mutated alleles vs. two mutated alleles: 9.5 +/- 5.8 vs. 17.8 +/- 8.9, p = 0.051). Therefore, the genotype of CYP2C19 is one of the important determinants of the plasma concentrations of AT and the capacity to desmethylate AT. Mother compound AT is shunted via hydroxylation pathways from AT to EHAT and ZHAT in the subjects with homozygotes of mutated alleles of CYP2C19 in order to compensate for the decreased capacity to desmethylate AT.

The value of haloperidol (HAL) in the treatment of schizophrenia and other psychiatric disorders has been well established. Its metabolism has been studied intensively. HAL is N-dealkylated to p-fluorobenzoylpropionic acid (FBPA) and to 4-(4-chlorophenyl) -4-hydroxypiperidene (CPHP), 1 reduction of the benzylic ketone produces reduced haloperidol (RHAL) by a cytosolic carbonyl reductase, 2 RHAL is reversely oxidated to HAL, 3 and HAL and RHAL undergo glucuronide conjugation. 4 Moreover, several other metabolic pathways of HAL are known, including formation of neurotoxic pyridinium metabolites by CYP3 A4.In vitro 3,5 and in vivo 6-8 studies suggested the involvement of CYP2D6 in HAL metabolism. Disposition of HAL is related to the polymorphic debrisoquine oxidation phenotype, 7 and the oxidation of RHAL to HAL is inhibited in vitro by quinidine, a potent inhibitor of CYP2D6, 3 although Young et al. have shown that quinidine does not affect the interconversion of HAL and RHAL. 9 CYP2D6 activity is reported in population studies to be bimodally distributed. Subjects who lack CYP2D6 activity are referred to as poor metabolizers, and they can be detected by screening for the specific alleles, Psychiatry and Clinical Neurosciences (1999) AbstractWe investigated the effect of cytochrome P450 (CYP2D6) genotypes on plasma levels of haloperidol (HAL) and reduced haloperidol (RHAL) in 47 Japanese male schizophrenic inpatients being treated with HAL. Mutation-specific polymerase chain reaction (PCR) analysis was used to detect CYP2D6*10 as the C188C1T mutation in exon 1. A long-PCR analysis method was used to detect CYP2D6*5. Allele frequencies of CYP2D6*5 and CYP2D6*10 were 4.3% and 34.0%, respectively. Plasma concentrations of HAL and RHAL were measured using high-performance liquid chromatography. The ranges of the plasma concentration of HAL and RHAL corrected to the dose were 0.28-1.60 (mean ± SD, 0.66 ± 0.25, n = 47) ng/mL/mg and 0.03-3.00 (mean ± SD, 0.36 ± 0.46, n = 47) ng/mL, respectively. Plasma RHAL/HAL ratios (R/H ratios) ranged from 0.06 to 1.88 (mean ± SD, 0.48 ± 0.32, n = 47). The analysis was performed among the four genotype groups:CYP2D6*1/CYP2D6*1 (n = 11), CYP2D6*1/CYP2D6*10 (n = 11), CYP2D6*10/CYP2D6*10 (n = 6) and those who have CYP2D6*5 allele (CYP2D6*1/ CYP2D6*5 or CYP2D6*5/CYP2D6*10 (n = 4). We observed significant tendency in effects of CYP2D6 genotypes on plasma concentration of HAL and significant effects on plasma concentration of RHAL, and R/H ratio. These results we obtained suggested that the plasma concentration of HAL and RHAL were determined partly by CYP2D6 polymorphic activity.

The impact of smoking on plasma haloperidol (HAL) concentrations was investigated in 66 Japanese male schizophrenic inpatients treated orally with HAL. The subjects consisted of 22 nonsmokers and 44 smokers each smoking ten cigarettes per day. Plasma concentrations of HAL were determined by an enzyme immunoassay method. There were significant positive correlations between the plasma HAL concentration and the daily dose of HAL per kg body weight (Y = 58.1X-0.01 (r = 0.86)). Smokers had significantly lower HAL concentrations per daily dose of HAL/kg body weight than nonsmokers (smokers vs. nonsmokers = 54.3+/-16.6 vs. 70.6+/-23.2 ng/mL/mg/kg). In doses less than 0.2 mg/kg of HAL, smokers showed significantly lower HAL concentrations per daily dose of HAL/kg body weight than nonsmokers (smokers vs. nonsmokers = 55.1+/-14.4 vs. 79.5+/-27.1 ng/mL/mg/kg), whereas no significant difference in HAL concentrations per daily dose of HAL/kg body weight was observed between smokers and nonsmokers when treated with more than 0.2 mg/kg (smokers vs. nonsmokers = 52.9+/-20.7 vs. 60.0+/-11.1 ng/mL/mg/kg). Our results indicate that smoking may induce the enzyme(s) metabolizing HAL, which results in lower plasma HAL concentrations in smokers than in nonsmokers, particularly at low doses of HAL.

The authors we investigated the relationship between plasma levels of haloperidol (HAL) and the number of CYP2D6*10 (*10) alleles in 66 Japanese inpatients with schizophrenia (male = 61, female = 5) on HAL. Plasma HAL level was determined by an enzyme immunoassay method. Daily dose of HAL was 1.5-36 (mean +/- SD = 12.3 +/- 7.6) mg or 0.02-0.49 (0.21 +/- 0.13) mg/kg body weight. Plasma HAL levels ranged from 1.4 to 47.4 (12.4 +/- 9.5) ng/mL. No significant difference in the plasma HAL levels was observed between the subjects with no, one, and two *10 alleles (one-way analysis of variance: 56.1 +/- 20.3, 61.0 +/- 20.3, and 63.3 +/- 20.3 ng/mL/mg/kg, respectively, F(2,63) = 0.65, p = 0.52). These results are not supportive of the previous report that plasma HAL levels can be predicted by the number of *10 alleles in Asian patients.

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.