Genta Hirokane

Lower plasma levels of haloperidol in smoking than in nonsmoking schizophrenic patients.

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 impact of CYP2C19 and CYP2D6 genotypes on metabolism of amitriptyline in Japanese psychiatric patients.

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 impact of CYP2D6 genotypes on the plasma concentration of paroxetine in Japanese psychiatric patients.

The authors investigated the impact of the CYP2D6 genotypes on the plasma concentration of paroxetine (PAX) in 55 Japanese psychiatric patients. They were administered 10 to 40 mg/day (24+/-10.0 mg/day) of PAX and maintained at the same daily dose for at least two weeks to obtain the steady-state concentrations. The plasma levels of PAX were 15.8+/-15.0, 47.4+/-32.0, 101.2+/-59.9 and 177.5+/-123.6 ng/ml at the daily dose of 10, 20, 30 and 40 mg, respectively, which suggested dose dependent kinetics of PAX. The allele frequencies of the CYP2D65, CYP2D610 and CYP2D641 were 1.8%, 41.8% and 1.8%, respectively. Significantly higher PAX concentrations were observed in the patients having one functional allele compared with those with two functional alleles (150.9+/-20.6 vs. 243.6+/-25.2 ng/ml mg(-1) kg(-1), p<0.05, Newman-Keuls multiple comparison test) or no functional (243.6+/-25.2 vs. 76.7+/-6.1 ng/ml mg(-1) kg(-1), p<0.05, Newman-Keuls multiple comparison test) in the subjects with 30 mg/day of paroxetine. The same trend of findings as in the subjects treated with 30 mg/day were observed in the subjects with 40 mg/day of PAX. The present results suggest that having one non-functional allele is the marker for high plasma concentration of PAX when relatively high daily dose of PAX is administered.

The effect of CYP2C19 and CYP2D6 genotypes on the metabolism of clomipramine in Japanese psychiatric patients.

In this study, the authors investigated the relationship between the metabolism of clomipramine (C) and the genotypes of cytochrome P450 (CYP) CYP2C19 and CYP2D6. Fifty-one Japanese patients (18 men and 33 women) were administered 10 to 250 mg/day of C by mouth and maintained on the same daily dose of C for at least 2 weeks to obtain steady-state concentrations. Plasma levels of C and its metabolites N-desmethylclomipramine (DC), 8-hydroxyclomipramine, and 8-hydroxy-N-desmethylclomipramine (HDC) were determined by high-performance liquid chromatography. The allele frequencies of CYP2C19*2, CYP2C19*3, CYP2D6*5, and CYP2D6*10 were 27.5%, 12.8%, 2.9%, and 43.1%, respectively. Subjects who were homozygous for mutated alleles of CYP2C19 showed approximately 75% higher concentrations of C corrected by dose and body weight compared with those who were homozygous for wild-type alleles. Also, subjects who were homozygous for mutated alleles of CYP2C19 showed an approximately 68% higher value of C/DC compared with those who were homozygous for wild-type alleles. No significant difference in the ratio of DC/HDC was observed between subjects who were homozygous for mutated alleles of CYP2D6 and those who were homozygous for wild-type alleles. These results suggest that genotyping CYP2C19 is useful for grossly predicting the risk of getting high plasma concentrations of C and the low individual capacity to demethylate C because there is marked interindividual variability within each genotype. However, the genotyping of CYP2D6 is not useful for predicting the individual capacity to hydroxylate DC.

The effect of cytochrome P450 2D6 genotypes on haloperidol metabolism: A preliminary study in a psychiatric population

We 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.

CYP2D6*10 alleles are not the determinant of the plasma haloperidol concentrations in Asian patients.

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.

Interindividual variation of plasma haloperidol concentrations and the impact of concomitant medications: the analysis of therapeutic drug monitoring data.

We analyzed therapeutic drug monitoring (TDM) data from 231 schizophrenic inpatients (137 men, 94 women) and investigated interindividual differences of plasma haloperidol (HAL) concentrations and drug/drug interactions between HAL and various concomitant drugs. Plasma HAL concentrations were determined by an enzyme immunoassay (EIA) method. Plasma HAL concentrations per daily dose of HAL per body weight (HAL C/D ratio) demonstrated an approximately 11-fold interindividual variation. The patient subjects who received carbamazepine (CBZ) concomitantly had a mean HAL C/D ratio that was 37% lower than that of the patient subjects without CBZ. The patient subjects treated with concomitant phenobarbital (PB) also showed a mean HAL C/D ratio that was 22% lower than those without PB. We concluded that careful evaluation of HAL TDM data and consideration of the impact of concomitant medication such as CBZ or PB that might influence the metabolism of HAL is necessary in daily clinical settings to avoid insufficient clinical response because of lowered concentrations of HAL or adverse effects because of high concentrations of HAL.

Effect of CYP2D6 genotypes on the metabolism of haloperidol in a Japanese psychiatric population

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±0.69 ng/ml/mg) and RHAL (1.10±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=0.68±0.31 ng/ml/mg, RHAL=0.28±0.37 ng/ml/mg), those with one CYP2D6*10 (HAL=0.70±0.23 ng/ml/mg, RHAL=0.31±0.16 ng/ml/mg) and those with two CYP2D6*10 alleles (HAL=0.69±0.14 ng/ml/mg, RHAL=0.40±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 (<10 mg/day), the subjects with two or one CYP2D6*10 allele(s) showed significantly higher plasma concentrations of RHAL (0.43±0.23 ng/ml/mg, 0.34±0.16 ng/ml/mg) than those without CYP2D6*10 allele (0.18±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.

Importance of the cytochrome P450 2D6 genotype for the drug metabolic interaction between chlorpromazine and haloperidol.

The authors studied the interactive effects of the coadministration of haloperidol and chlorpromazine on plasma concentrations of haloperidol and reduced haloperidol. The subjects were 43 Japanese male schizophrenic inpatients who were concomitantly treated with chlorpromazine before or after monotherapy with haloperidol. Coadministration of chlorpromazine produced significant increases in the plasma concentrations of haloperidol (P < 0.01) and reduced haloperidol (P < 0.001) by an average of 28.5% ± 83.3% and 160.8% ± 288.9%, respectively. However, there were marked interindividual variations in the interactive effects of chlorpromazine. The authors analyzed the importance of five CYP2D6 genotypes, *1/ *1, *1/ *10, *10/ *10, *1/*5, and *5/*10 on the percentage of change in plasma concentrations of haloperidol and reduced haloperidol. Patients with the CYP2D6*5 allele (n = 4) showed a significantly smaller increase in plasma concentrations of haloperidol (P < 0.05) and a slightly smaller increase in those of reduced haloperidol (P = 0.074) in response to the coadministration of chlorpromazine compared than those with the CYP2D6*1/*1 genotype (n = 8). Those with the CYP2D6*1/*1 genotype (n = 8) showed a trend toward greater increases in plasma concentrations of haloperidol than those with other genotypes (P = 0.087).

Genetic and pharmacokinetic factors affecting the initial pharmacotherapeutic effect of paroxetine in Japanese patients with panic disorder

ObjectiveThe objective of this study was to evaluate genetic and pharmacokinetic factors affecting the initial pharmacotherapeutic effect of paroxetine (PAX) in Japanese patients with panic disorder (PD).MethodPlasma concentration of PAX was determined by high performance liquid chromatography. Serotonin transporter gene-linked polymorphic region (5-HTTLPR) variants were determined by polymerase chain reaction techniques. PD severity was assessed using the Panic and Agoraphobia Scale (PAS).ResultsMultiple regression analysis revealed that the plasma concentration of PAX, 5-HTTLPR genotype, and comorbid physical illness were significant factors affecting the initial pharmacotherapeutic effect of PAX in PD and indicated that these factors accounted for 52.4% (R2 = 0.524) of the variability in the percent reduction in PAS score. The final model was described by the following equation (P = 0.001): percent reduction in PAS score (%) = 68.5 − 1.2 × [plasma concentration of PAX (ng/ml)] − 33.0 × (L/S = 1, S/S = 0) − 21.8 × (with comorbid physical illness = 1, without comorbid physical illness = 0).ConclusionThe high plasma concentration of PAX, the L/S genotype of 5-HTTLPR, and comorbid physical illness might be associated with a poor response to the initial phase of pharmacotherapy of PD with PAX.