Toshiaki Aoshima

Pharmacogenetics of classical and new antipsychotic drugs.

Several classical antipsychotic drugs, i.e., chlorpromazine, haloperidol, perphenazine, thioridazine and zuclopenthixol; and some new neuroleptic drugs, i.e., risperidone and sertindole, are metabolized predominantly by cytochrome P450 (CYP) 2D6. Significant relationships have been reported between the steady state plasma concentrations (Css) of some classical neuroleptics and the CYP2D6 activity or genotype. Several of these drugs also potently inhibit the CYP2D6 activity. These facts explain several drug metabolic interactions of the classical drugs. Two studies failed to show that the CYP2D6 activity predicts the therapeutic effects of haloperidol or perphenazine. Some studies have suggested that the poor metabolizer phenotype is associated with the development of oversedation during treatment with the classical drugs, but other studies have been inconsistent or negative. The CYP2D6 phenotyping and genotyping appear to be useful in predicting the Css of some classical drugs, but their usefulness in predicting clinical effects must be further explored.

Effects of the CYP 2D6 genotype and cigarette smoking on the steady-state plasma concentrations of fluvoxamine and its major metabolite fluvoxamino acid in Japanese depressed patients.

&NA; The effects of the cytochrome P450 (CYP) 2D6 genotype and cigarette smoking on the steady‐state plasma concentrations (Css) of fluvoxamine (FLV) and its demethylated metabolite fluvoxamino acid (FLA) were studied in 49 Japanese depressed patients receiving FLV 200 mg/d. The Css of FLV and FLA were measured by HPLC, and the wild‐type allele (*1) and two mutated alleles causing absent (*5) or decreased (*10) CYP 2D6 activity were identified by PCR methods. The patients were divided into three genotype groups by the number of mutated alleles: 12 cases with no (*1/*1), 27 cases with one (*1/*5 and *1/*10), and 10 cases with two (*5/*10 and *10/*10) mutated alleles. The means ± SD of the Css of FLV and FLA and the FLA/FLV ratio of all patients were 169.1 ± 147.5 ng/mL, 83.9 ± 52.7 ng/mL, and 0.71 ± 0.50, respectively. The Css of FLV and FLA were not significantly different among the three genotype groups. However, the FLA/FLV ratio was significantly lower in the patients with one (P < 0.05) and two (P < 0.01) mutated alleles than in those with no mutated allele. There was no significant difference between nonsmokers (n = 34) and smokers (n = 15) in these values. In the stepwise multiple regression, the Css of FLA (P < 0.05) and FLA/FLV ratio (P < 0.001) showed significant negative correlations with the number of mutated alleles, and the FLA/FLV ratio was significantly (P < 0.05) lower in women than in men. The present study suggests that the CYP 2D6 genotype and cigarette smoking have no major impact on the Css of FLV and FLA, though CYP 2D6 is involved in the demethylation of FLV.

Single oral dose pharmacokinetics of quazepam is influenced by CYP2C19 activity

The effects of cytochrome P450 (CYP)2C19 activity and cigarette smoking on the single oral dose pharmacokinetics of quazepam were studied in 20 healthy Japanese volunteers. Twelve subjects were extensive metabolizers (EMs), and 8 subjects were poor metabolizers (PMs) by CYP2C19 as determined by the PCR-based genotyping. Nine subjects were smokers (>10 cigarettes/d), and 11 subjects were nonsmokers. The subjects received a single oral 20-mg dose of quazepam, and blood samplings and evaluation of psychomotor function were conducted up to 72 hours after dosing. Plasma concentrations of quazepam and its active metabolite 2-oxoquazepam (OQ) were measured by HPLC. There were significant differences between EMs and PMs in the peak plasma concentration (mean ± SD: 34.5 ± 16.6 versus 66.2 ± 19.2 ng/mL, P < 0.01) and total area under the plasma concentration–time curve (490.1 ± 277.5 vs 812.1 ± 267.2 ng · h/mL, P < 0.05) of quazepam. The pharmacokinetic parameters of OQ and pharmacodynamic parameters were not different between the 2 groups. Smoking status did not affect the pharmacokinetic parameters of quazepam and OQ or pharmacodynamic parameters. The present study suggests that the single oral dose pharmacokinetics of quazepam are influenced by CYP2C19 activity but not by cigarette smoking.

Effects of itraconazole on the plasma kinetics of quazepam and its two active metabolites after a single oral dose of the drug

&NA; The effects of itraconazole, a potent inhibitor of cytochrome P450 (CYP) 3A4, on the plasma kinetics of quazepam and its two active metabolites after a single oral dose of the drug were studied. Ten healthy male volunteers received itraconazole 100 mg/d or placebo for 14 days in a double‐blind randomized crossover manner, and on the fourth day of the treatment they received a single oral 20‐mg dose of quazepam. Blood samplings and evaluation of psychomotor function by the Digit Symbol Substitution Test and Stanford Sleepiness Scale were conducted up to 240 h after quazepam dosing. Itraconazole treatment did not change the plasma kinetics of quazepam but significantly decreased the peak plasma concentration and area under the plasma concentration‐time curve of 2‐oxoquazepam and N‐desalkyl‐2‐oxoquazepam. Itraconazole treatment did not affect either of the psychomotor function parameters. The present study thus suggests that CYP 3A4 is partly involved in the metabolism of quazepam.

Interaction Study Between Enoxacin and Fluvoxamine

Authors examined a possible interaction between enoxacin, an inhibitor of cytochrome P4501A2, and fluvoxamine (FLV), a substrate for this enzyme. Ten healthy male volunteers received enoxacin 200 mg/d or placebo for 11 days in a double-blind randomized crossover manner, and on the eighth day they received a single oral 50-mg dose of FLV. Blood samplings and pharmacodynamic evaluation were conducted up to 72 hours after FLV dosing. Plasma concentrations of FLV and its active metabolite fluvoxamino acid (FLA) were measured by high-performance liquid chromatography. Enoxacin significantly increased the plasma concentrations at 2 hours (placebo versus enoxacin, mean ± SD: 4.4 ± 2.4 vs 7.0 ± 4.1 ng/mL, P < 0.05) and 3 hours (7.4 ± 2.7 vs 11.2 ± 3.8 ng/mL, P < 0.01) and the Cmax (10.2 ± 2.9 vs 11.6 ± 4.0 ng/mL, P < 0.05) of FLV. Plasma concentration and pharmacokinetic parameters of FLA were not affected by enoxacin. Enoxacin significantly (P < 0.05) increased the scores of the Stanford Sleepiness Scale from 0.5 to 4 hours, suggesting that enoxacin increased the sleepiness produced by FLV. The present study suggests that enoxacin slightly inhibits the metabolism of FLV, and enoxacin should be combined with FLV with caution.

Dose-dependent augmentation effect of bromocriptine in a case with refractory depression

1. A 52-year-old female with refractory depression had not responded to various treatments including electroconvulsive therapy and augmentation therapy with lithium or triiodothyronine. 2. Addition of bromocriptine 2.5-5 mg/day to imipramine improved her depressive symptoms. However, when the dose was increased to 15 mg/day to treat residual depressive symptoms, her clinical status deteriorated and returned to the original level. The dose reduction to 5mg/day again improved her depressive symptoms. 3. This report confirms the augmentation effect of bromocriptine for refractory depression. It also suggests that there is dose-dependency in this effect.

Effects of the CYP2C19 genotype and cigarette smoking on the single oral dose pharmacokinetics and pharmacodynamics of estazolam

The effects of the cytochrome P450 (CYP)2C19 genotype and cigarette smoking on the single oral dose pharmacokinetics and pharmacodynamics of estazolam were studied in 16 healthy male volunteers. The two mutated alleles (CYP2C19*2 and CYP2C19*3) causing absent CYP2C19 activity were identified by PCR-based restriction enzyme analysis. Five subjects had no mutated allele, five had one mutated allele, and six had two mutated alleles. Seven subjects were smokers, and nine were nonsmokers. The subjects received a single oral 4-mg dose of estazolam, and blood samplings and evaluation of psychomotor function were conducted up to 72 h after dosing. There was no significant difference among the groups with no, one, and two mutated alleles for the peak plasma concentration (145.2+/-36.5 vs. 142.1+/-33.6 vs. 113.2+/-29.7 ng/ml), area under the plasma concentration-time curve (0- infinity ) (4916.0+/-1276.4 vs. 4389.6+/-736.1 vs. 4047.3+/-613.8 ng x h/ml), apparent oral clearance (0.22+/-0.05 vs. 0.25+/-0.03 vs. 0.25+/-0.03 ml/min/kg), and elimination half-life (24.4+/-4.6 vs. 29.6+/-8.5 vs. 30.7+/-3.9 h). Similarly, none of the pharmacokinetic parameters was significantly different between the nonsmoker and smoker groups. Neither the number of mutated allele nor cigarette smoking affected the psychomotor function parameters significantly. The present study suggests that neither the CYP2C19 genotype nor cigarette smoking affects the single oral dose pharmacokinetics and pharmacodynamics of estazolam.

No effect of itraconazole on the single oral dose pharmacokinetics and pharmacodynamics of estazolam.

To examine the involvement of cytochrome P450 3A4 in the metabolism of estazolam, the effect of itraconazole, a potent inhibitor of this enzyme, on the single oral dose pharmacokinetics and pharmacodynamics of estazolam was studied in a double-blind randomized crossover manner. Ten healthy male volunteers received itraconazole 100 mg/day or placebo orally for 7 days, and on the 4th day they received a single oral 4-mg dose of estazolam. Blood samplings and evaluation of psychomotor function by the Digit Symbol Substitution Test, Visual Analog Scale, and Stanford Sleepiness Scale were conducted up to 72 hours after estazolam dosing. There was no significant difference between the placebo and itraconazole phases for the peak plasma concentration, apparent oral clearance, and elimination half-life. Similarly, none of the psychomotor function parameters was significantly different between the two phases. The current study showed no significant effect of itraconazole on the single oral dose pharmacokinetics and pharmacodynamics of estazolam, suggesting that cytochrome P450 3A4 is not involved in the metabolism of estazolam to a major extent.

No association between the TPH A218C polymorphism and personality traits in Japanese healthy subjects

It has been suggested that the central serotonergic activity is implicated in personality traits. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in serotonin synthesis. In the present study, the association between the TPH A218C polymorphism and personality traits assessed by the Temperament and Character Inventory (TCI) was examined in 345 Japanese healthy subjects. The TPH A218C polymorphism was determined by a PCR-RFLP method. There were no significant differences in the seven dimension scores of TCI among the A/A, A/C, and C/C genotype groups by the one-way ANOVA. There was a significant negative correlation between age and the NS scores. Females showed significantly higher scores of HA, RD, and ST, and significantly lower scores of SD than males. The multiple regression analysis using age, gender, and the TPH genotype as independent variables also showed no significant association between any dimension score and the genotype. The present study thus suggests that the TPH A218C polymorphism does not affect personality traits in Japanese healthy subjects.

Interaction Study between Fluvoxamine and Quazepam

It has been reported that fluvoxamine, an inhibitor of various cytochrome P450 enzymes, markedly inhibits the metabolism of several drugs. The purpose of the present study was to examine a possible interaction between fluvoxamine and quazepam. Twelve healthy male volunteers received fluvoxamine 50 mg/day or placebo for 14 days in a double‐blind randomized crossover manner, and on the 4th day they received a single oral 20‐mg dose of quazepam. Blood samplings and evaluation of psychomotor function by the Digit Symbol Substitution Test and Stanford Sleepiness Scale were conducted up to 240 hours after quazepam dosing. Plasma concentrations of quazepam and its active metabolites 2‐oxoquazepam (OQ) and N‐desalkyl‐2‐oxoquazepam (DOQ) were measured by high‐performance liquid chromatography (HPLC). Fluvoxamine did not change plasma concentrations of quazepam but significantly decreased those of OQ from 6 to 12 hours and those of DOQ from 3 to 48 hours. The AUC ratio of OQ to quazepam was significantly lower in the fluvoxamine phase. Fluvoxamine did not affect psychomotor function at most of the time points. The present study suggests that fluvoxamine slightly inhibits the metabolism of quazepam to OQ, but this interaction appears to have minimal clinical significance.