Norio Yasui-Furukori

Different effects of three transporting inhibitors, verapamil, cimetidine, and probenecid, on fexofenadine pharmacokinetics

Fexofenadine is a substrate of P‐glycoprotein and organic anion transporting polypeptides. The aim of this study was to compare the inhibitory effects of different transporting inhibitors on fexofenadine pharmacokinetics.

Genomewide High-Density SNP Linkage Analysis of 236 Japanese Families Supports the Existence of Schizophrenia Susceptibility Loci on Chromosomes 1p, 14q, and 20p

The Japanese Schizophrenia Sib-Pair Linkage Group (JSSLG) is a multisite collaborative study group that was organized to create a national resource for affected sib pair (ASP) studies of schizophrenia in Japan. We used a high-density single-nucleotide-polymorphism (SNP) genotyping assay, the Illumina BeadArray linkage mapping panel (version 4) comprising 5,861 SNPs, to perform a genomewide linkage analysis of JSSLG samples comprising 236 Japanese families with 268 nonindependent ASPs with schizophrenia. All subjects were Japanese. Among these families, 122 families comprised the same subjects analyzed with short tandem repeat markers. All the probands and their siblings, with the exception of seven siblings with schizoaffective disorder, had schizophrenia. After excluding SNPs with high linkage disequilibrium, we found significant evidence of linkage of schizophrenia to chromosome 1p21.2-1p13.2 (LOD=3.39) and suggestive evidence of linkage to 14q11.2 (LOD=2.87), 14q11.2-q13.2 (LOD=2.33), and 20p12.1-p11.2 (LOD=2.33). Although linkage to these regions has received little attention, these regions are included in or partially overlap the 10 regions reported by Lewis et al. that passed the two aggregate criteria of a meta-analysis. Results of the present study--which, to our knowledge, is the first genomewide analysis of schizophrenia in ASPs of a single Asian ethnicity that is comparable to the analyses done of ASPs of European descent--indicate the existence of schizophrenia susceptibility loci that are common to different ethnic groups but that likely have different ethnicity-specific effects.

Effect of verapamil on pharmacokinetics and pharmacodynamics of risperidone: In vivo evidence of involvement of P-glycoprotein in risperidone disposition

A recent in vitro study has shown that risperidone is a substrate of P‐glycoprotein. The aim of this study was to confirm the effects of verapamil, a P‐glycoprotein inhibitor, on the pharmacokinetics of risperidone.

The -141C Ins/Del polymorphism in the dopamine D2 receptor gene promoter region is associated with anxiolytic and antidepressive effects during treatment with dopamine antagonists in schizophrenic patients

Previous studies have demonstrated a lower density of dopamine D2 receptor (DRD2) in subjects without Del alleles of the -141C Ins/Del polymorphism in DRD2 gene promoter region than in those with one or two Del alleles. The present study aimed to examine whether the -141C Ins/Del DRD2 promoter polymorphism is related to therapeutic response to selective DRD2 antagonists in the treatment of schizophrenia. Subjects consisted of 49 acutely exacerbated schizophrenic inpatients treated with bromperidol (30 cases, mean dose +/- SD: 11.4 +/- 4.8 mg/day) or nemonapride (19 cases, 18 mg/day). Clinical symptoms were evaluated by the Brief Psychiatric Rating Scale (BPRS) before and 3 weeks after the treatment. The -141C Ins/Del DRD2 genotypes, the Ins and Del alleles, were determined by a polymerase chain reaction method. Thirty-five patients were homozygous for the Ins allele and 14 were heterozygous for the Del and Ins alleles. The patients without Del allele showed a higher percentage of improvement in anxiety-depression symptoms than those with Del allele (58.5 +/- 44.5% versus 24.1 +/- 48.2%) after 3 weeks of treatment while percentage improvement in total BPRS or other subgrouped symptoms (positive, negative, excitement and cognitive symptoms) was similar between the two genotype groups. The present results suggest that the -141C Ins/Del DRD2 polymorphism is associated with anxiolytic and antidepressive effects of neuroleptic treatment in schizophrenic patients.

The effect of aging on the relationship between the cytochrome P450 2C19 genotype and omeprazole pharmacokinetics.

Background and objectiveThe metabolic activity of cytochrome P450 (CYP) 2C19 is genetically determined, and the pharmacokinetics of omeprazole, a substrate for CYP2C19, are dependent on the CYP2C19 genotype. However, a discrepancy between the CYP2C19 genotype and omeprazole pharmacokinetics was reported in patients with liver disease or advanced cancer. The objective of the present study was to evaluate the effect of aging on the relationship between the CYP2C19 genotype and its phenotype.MethodsTwenty-eight elderly and 23 young Japanese volunteers were enrolled after being genotyped. Each subject received a single intravenous dose of omeprazole (10mg and 20mg for the elderly and the young groups, respectively) and blood samples were obtained up to 6 hours after dose administration to determine the plasma concentrations of omeprazole and its metabolites, 5-hydroxyomeprazole and omeprazole sulfone. Pharmacokinetic parameters were obtained by noncompartmental analysis. Linear regression models were used to examine the joint effects of covariates such as genotype, age, etc., on the pharmacokinetic parameters, and the pharmacokinetic parameters showing statistical significance were compared by ANOVA.ResultsThere were significant differences between genotypes in the area under the plasma concentration-time curve of the young group and the elderly group. The number of mutation alleles and age were significant covariates for systemic clearance (CL), but age was the only significant covariate for volume of distribution at steady state (Vss). There were significant age- and genotype-related differences and a significant age × genotype interaction in CL (20.6 ± 11.0/12.7 ± 4.0/3.2 ± 1.0 and 5.4 ± 4.0/3.7 ± 1.4/2.1 ± 0.7 L/h for homozygous extensive metabolisers [EMs]/heterozygous EMs/poor metabolisers [PMs] of the young and the elderly groups, respectively). In Vss, a significant difference was found between the young and the elderly groups (219 ± 115 and 107 ± 44.5 mL/kg, respectively), but not between three genotypes (178 ± 142, 173 ± 79 and 110 ± 51 mL/kg for homozygous EMs, heterozygous EMs and PMs, respectively).ConclusionThe elderly EMs showed wide variance in the in vivo CYP2C19 activity and were phenotypically closer to the elderly PMs than the young EMs were to the young PMs. Some of the elderly homozygous EMs, as well as heterozygous EMs, have a metabolic activity similar to PMs, and the CYP2C19 genotype may therefore not be as useful as phenotyping in the elderly.

Relationship between functional dopamine D2 and D3 receptors gene polymorphisms and neuroleptic malignant syndrome

Our previous study has suggested that the TaqI A polymorphism of dopamine D2 receptor gene (DRD2) is associated with the predisposition to neuroleptic malignant syndrome (NMS). However, the specificity of this polymorphism as a predictor of NMS dose not seem to be sufficient enough. Meanwhile, it has been shown that the non‐carriers of Del allele of the −141C Ins/Del polymorphism in the promoter region of DRD2 have lower dopamine D2 receptor in the brain than the carriers. In addition, dopamine D3 receptor gene has a Ser9Gly polymorphism, which may alter the receptor function. The present study examined the association between these three polymorphisms and the development of NMS to investigate if a combination of these polymorphisms could increase the specificity as markers for NMS. The subjects were 17 psychiatric patients who had developed NMS (13 patients with schizophrenia, 3 with major depression, and 1 with dementia of the Alzheimers type) and 163 schizophrenic patients who had never developed this syndrome. The frequency of the A1 allele was significantly (P = 0.012) higher in the patients who had developed NMS (59%) than in the patients who had not (35%). The proportion of the A1 carriers was significantly (P = 0.003) higher in the patients with NMS (16/17: 94%) than in those without the syndrome (93/163: 57%). However, no significant differences were found in the allele and genotype frequencies of the other two polymorphisms between the two groups. The present study suggests that only the TaqI A polymorphism is at least partly useful as a predictor of NMS, but the −141 C Ins/Del and Ser9Gly polymorphisms are not.

Dose-Dependent Effects of Adjunctive Treatment With Aripiprazole on Hyperprolactinemia Induced by Risperidone in Female Patients With Schizophrenia

Hyperprolactinemia is a frequent consequence of treatment with risperidone. Recent studies have suggested that aripiprazole, a partial dopamine agonist, reduces the prolactin response to antipsychotics. Thus, we examined the dose effects of adjunctive treatment with aripiprazole on the plasma concentration of prolactin in patients who had elevated prolactin levels because of risperidone treatment. Aripiprazole was concomitantly administrated to 16 female patients with schizophrenia receiving 2 to 15 mg/d of risperidone. Dosages of aripiprazole were gradually increased from 3 to 12 mg/d with 2- to 4-week intervals. Sample collections for prolactin were conducted before aripiprazole administration (baseline) and 2 to 4 weeks after the dose escalation of aripiprazole and just before next dose escalation. The samples were taken just before the morning dose. The plasma concentration of prolactin during aripiprazole administration (3, 6, 9, or 12 mg/d) was significantly lower than that at baseline. The mean (±SD) percent reductions at 3, 6, 9, and 12 mg/d were 35% ± 14%, 54% ± 17%, 57% ± 19%, and 63% ± 17%, respectively. However, neither the plasma concentration of prolactin nor the reduction ratio differed among the dosages of 6, 9, and 12 mg/d of aripiprazole. Three out of 8 patients with amenorrhea improved after 12 mg/d of aripiprazole. The present study suggests that adjunctive treatment with aripiprazole reduces the prolactin concentration that had been increased because of risperidone treatment. The effect occurs even when a low dosage (3 mg/d) of aripiprazole was used and achieves a plateau at dosages beyond 6 mg/d.

Effects of various CYP2D6 genotypes on the steady-state plasma concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone, in Japanese patients with schizophrenia.

The effects of various CYP2D6 genotypes on the steady-state plasma concentrations (Css) of risperidone and its active metabolite, 9-hydroxyrisperidone, were studied in 85 Japanese schizophrenic patients (27 men and 58 women) treated with 6 mg/d risperidone for at least 2 weeks. Plasma concentrations of risperidone and 9-hydroxyrisperidone were measured using liquid chromatography–tandem mass spectrometry. The patients had the following CYP2D6 genotypes: wild-type (wt) /wt (40 patients), CYP2D6 * 10 (* 10)/ wt (28), CYP2D6 * 5 (* 5)/ wt (8), * 10/ * 10 (5), * 5/ * 10 (3), and CYP2D6 * 4/CYP2D6 * 14 (1), respectively. The Css values of risperidone and 9-hydroxyrisperidone were corrected to the median body weight of 58 kg. The medians (ranges) of the Css of risperidone in the aforementioned genotype groups were 2.2 (0.37–35.7), 6.4 (2.1–26.5), 12.3 (4.7–39.5), 19.4 (13.4–26.4), 64.0 (41.6–68.8), and 91.8 nmol/L. Those values for risperidone-to-9-hydroxyrisperidone ratio were 0.03 (0.01–0.33), 0.06 (0.03–0.19), 0.14 (0.07–0.29), 0.28 (0.25–0.38), 0.48 (0.38–0.58), and 2.35, respectively. The Css of risperidone was significantly (P < 0.05 or P < 0.001) different among the four genotype groups (wt/wt, * 10/wt, * 5/wt, and * 10/ * 10), except between the * 5/wt and * 10/ * 10 groups. Also, the risperidone-to-9-hydroxyrisperidone ratio significantly (P < 0.005 or P < 0.001) differed among these genotype groups. No significant differences were found in the Css of 9-hydroxyrisperidone and the active moiety (the Css of risperidone plus 9-hydroxyrisperidone) among these genotype groups. This study confirms previous findings that the CYP2D6 status affects the Css of risperidone via its strong regulation of 9-hydroxylation of risperidone. However, similar active moiety of risperidone among different genotype groups suggests that the determination of the CYP2D6 genotype has little importance for clinical situations.

Effects of Fluvoxamine on Lansoprazole Pharmacokinetics in Relation to CYP2C19 Genotypes

Lansoprazole is a substrate of CYP2C19 and CYP3A4. The aim of this study was to compare the inhibitory effects of fluvoxamine, an inhibitor of CYP2C19, on the metabolism of lansoprazole between CYP2C19 genotypes. Eighteen volunteers—of whom 6 were homozygous extensive metabolizers (EMs), 6 were heterozygous EMs, and 6 were poor metabolizers (PMs) for CYP2C19—received three 6‐day courses of either daily 50 mg fluvoxamine or placebo in a randomized fashion with a single oral 60‐mg dose of lansoprazole on day 6 in all cases. Plasma concentrations of lansoprazole and its metabolites, 5‐hydroxylansoprazole and lansoprazole sulfone, were monitored up to 24 hours after the dosing. During placebo administration, there was a significant difference in the area under the plasma concentration‐time curve from time 0 to infinity (AUC0‐∞) of lansoprazole between CYP2C19 genotypes. Fluvoxamine treatment increased AUC0‐∞ of lansoprazole by 3.8‐fold (P < .01) in homozygous EMs and by 2.5‐fold (P < .05) in heterozygous EMs, whereas no difference in any pharmacokinetic parameters was found in PMs. There was a significant difference in the fluvoxamine‐mediated percentage increase in the AUC0‐∞ of lansoprazole between CYP2C19 genotypes. The present study indicates that there are significant drug interactions between lansoprazole and fluvoxamine in EMs. CYP2C19 is predominantly involved in lansoprazole metabolism in EMs.

Effects of CYP2D6 Genotypes on Plasma Concentrations of Risperidone and Enantiomers of 9‐Hydroxyrisperidone in Japanese Patients with Schizophrenia

It has been shown that risperidone (+)‐9‐hydroxylation is enantioselectively catalyzed by the polymorphic CYP2D6 in human liver. This study aimed to examine the effect of CYP2D6 genotype on (+)‐9‐hydroxylation of risperidone in schizophrenic patients. Subjects were 38 Japanese schizophrenic inpatients receiving 6 mg/day of risperidone. Plasma concentrations of risperidone and (+)‐ and (−)‐9‐hydroxyrisperidone at steady state were quantified using LC/MS/MS and HPLC with α1 acid‐AGP chiral column, respectively. The CYP2D6*5(*5) and *10 alleles were identified using polymerase chain reaction (PCR) methods. Twenty patients had no mutated allele, 14 had one mutated allele, and 4 had two mutated alleles. There were significant differences in the steady‐state plasma concentrations of risperidone (ANOVA; p < 0.0001) among the three genotype groups, while the CYP2D6 genotype did not affect the steady‐state plasma concentrations of (+)‐9‐hydroxyrisperidone (p = 0.314) or (−)‐9‐hydroxyrisperidone (p = 0.957). The concentration ratio of risperidone to 9‐hydroxyrisperidone was strongly dependent on the CYP2D6 genotypes. This study suggests that CYP2D6 activity strongly influences the steady‐state plasma concentrations of risperidone and risperidone/9‐hydroxyrisperidone concentration ratios but is unlikely to determine enantioselectivity in the steady‐state plasma concentrations of 9‐hydroxyrisperidone in the clinical situation.