| 1 | Ther Drug Monit 2008 Oct 30: 628-33 |
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| PMID | 18708991 |
| Title | ABCB1 polymorphisms influence steady-state plasma levels of 9-hydroxyrisperidone and risperidone active moiety. |
| Abstract | Risperidone is metabolized to its active metabolite, 9-hydroxyrisperidone, mainly by the cytochrome P450 enzymes CYP2D6 and 3A4. Its antipsychotic effect is assumed to be related to the active moiety, that is, the sum of risperidone and 9-hydroxyrisperidone. Both risperidone and 9-hydroxyrisperidone are substrates of P-glycoprotein (P-gp), a transport protein involved in drug absorption, distribution, and elimination. The aim of the present study was to evaluate the influence of polymorphisms in genes encoding CYP3A5 and P-gp (ABCB1) on the steady-state plasma levels of risperidone, 9-hydroxyrisperidone, and the active moiety, taking CYP2D6 genotype status into account. Forty-six white patients with schizophrenia treated with risperidone (1-10 mg/d) in monotherapy for 4-6 weeks were genotyped, and their plasma concentrations of risperidone and 9-hydroxyrisperidone were measured. Dose-corrected plasma concentrations (C/D) of risperidone, 9-hydroxyrisperidone, and active moiety showed up to 68-, 9-, and 10-fold interindividual variation, respectively. Six patients carried 1 CYP3A5*1 allele and therefore were likely to express the CYP3A5 enzyme. The CYP3A5 genotype did not influence risperidone, 9-hydroxyrisperidone, or active moiety C/Ds. The CYP2D6 genotype in these 46 patients was again associated with risperidone C/D (P = 0.001) but not with 9-hydroxyrisperidone C/D or active moiety C/D, as previously shown by our group in 37 of these patients. Patients homozygous for the ABCB1 3435T/2677T/1236T haplotype had significantly lower C/Ds of 9-hydroxyrisperidone (P = 0.026) and active moiety (P = 0.028) than patients carrying other ABCB1 genotypes. In conclusion, our results confirmed the significant effect of CYP2D6 genotype on the steady-state plasma levels of risperidone and showed that ABCB1 polymorphisms have a moderate effect on those of 9-hydroxyrisperidone and the active moiety. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 2 | Pharmacogenet. Genomics 2008 Jul 18: 599-609 |
| PMID | 18551040 |
| Title | Naturalistic pharmacogenetic study of treatment resistance to typical neuroleptics in European-Brazilian schizophrenics. |
| Abstract | This study aimed to explore the influence of variation in DRD2, DRD3, CYP2D6, CYP3A4, and CYP3A5 genes on treatment resistance to typical neuroleptics in a Brazilian sample of patients with schizophrenia. One polymorphism at DRD2 gene, five at DRD3, 24 at CYP2D6, nine at CYP3A4 gene, and one at CYP3A5 gene were genotyped in a sample of 186 patients with schizophrenia. From the nine studied CYP3A4 single nucleotide polymorphisms, only the -392A>G was polymorphic, and significant associations were observed between this single nucleotide polymorphism and efficacy of neuroleptic treatment. Homozygous individuals for the -392A variant [P=0.014, odds ratio (OR)=3.32] were more frequent in the treatment-resistant group, compared with carriers of one copy of the -392G variant. The CYP3A5 low expressor genotype (CYP3A5*3/CYP3A5*3) was found to be associated with refractoriness to neuroleptic treatment (P=0.003, OR=3.16). Among the haplotypes observed in DRD3 gene, the T/A/G/A/C haplotype showed an association with refractoriness to neuroleptics (chi=5.342, P=0.021, OR=1.75). This association showed that carriers of one copy of this haplotype presented intermediate values between noncarriers and homozygous individuals for the haplotype. No association was observed with polymorphisms in DRD2 and CYP2D6 genes. Multiple logistic regression analyses showed that the number of copies of DRD3 T/A/G/A/C haplotype and CYP3A5 low expressor genotype were predictors of refractoriness to neuroleptic after controlling for selected risk factors. CYP3A5*3 individuals carrying at least one copy of the T/A/G/A/C haplotype showed a higher risk to be refractory to neuroleptics than CYP3A5*3 homozygotes+non-T/A/G/A/C carriers (chi=5.533, P=0.019, OR=2.32, 95% confidence interval=1.08-5.02). No significant associations were observed with DRD2 and CYP2D6 polymorphisms. Our results suggest a role for CYP3A5 and DRD3 gene variants on refractoriness to neuroleptic treatment in Brazilians with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 3 | Pharmacogenet. Genomics 2008 Jul 18: 599-609 |
| PMID | 18551040 |
| Title | Naturalistic pharmacogenetic study of treatment resistance to typical neuroleptics in European-Brazilian schizophrenics. |
| Abstract | This study aimed to explore the influence of variation in DRD2, DRD3, CYP2D6, CYP3A4, and CYP3A5 genes on treatment resistance to typical neuroleptics in a Brazilian sample of patients with schizophrenia. One polymorphism at DRD2 gene, five at DRD3, 24 at CYP2D6, nine at CYP3A4 gene, and one at CYP3A5 gene were genotyped in a sample of 186 patients with schizophrenia. From the nine studied CYP3A4 single nucleotide polymorphisms, only the -392A>G was polymorphic, and significant associations were observed between this single nucleotide polymorphism and efficacy of neuroleptic treatment. Homozygous individuals for the -392A variant [P=0.014, odds ratio (OR)=3.32] were more frequent in the treatment-resistant group, compared with carriers of one copy of the -392G variant. The CYP3A5 low expressor genotype (CYP3A5*3/CYP3A5*3) was found to be associated with refractoriness to neuroleptic treatment (P=0.003, OR=3.16). Among the haplotypes observed in DRD3 gene, the T/A/G/A/C haplotype showed an association with refractoriness to neuroleptics (chi=5.342, P=0.021, OR=1.75). This association showed that carriers of one copy of this haplotype presented intermediate values between noncarriers and homozygous individuals for the haplotype. No association was observed with polymorphisms in DRD2 and CYP2D6 genes. Multiple logistic regression analyses showed that the number of copies of DRD3 T/A/G/A/C haplotype and CYP3A5 low expressor genotype were predictors of refractoriness to neuroleptic after controlling for selected risk factors. CYP3A5*3 individuals carrying at least one copy of the T/A/G/A/C haplotype showed a higher risk to be refractory to neuroleptics than CYP3A5*3 homozygotes+non-T/A/G/A/C carriers (chi=5.533, P=0.019, OR=2.32, 95% confidence interval=1.08-5.02). No significant associations were observed with DRD2 and CYP2D6 polymorphisms. Our results suggest a role for CYP3A5 and DRD3 gene variants on refractoriness to neuroleptic treatment in Brazilians with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 4 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2009 Oct 33: 1200-4 |
| PMID | 19591893 |
| Title | A case-control association study between the CYP3A4 and CYP3A5 genes and schizophrenia in the Chinese Han population. |
| Abstract | In this study, variants of two genes coding for cytochrome P450 enzyme (CYP3A4 and CYP3A5) were analysed in a case-control sample using 398 schizophrenic patients and 391 healthy controls. All subjects were unrelated Han Chinese from Shanghai. No difference was observed on the allelic or genotypic distribution of CYP3A4 and CYP3A5 gene polymorphisms between the groups. However, the two-marker haplotypes covering components CYP3A41G and CYP3A53 were observed to be significantly associated with schizophrenia (corrected global p=0.0009). In addition, we identified one common risk haplotype, G/G (present in 59.5% of the general population). The results suggest that CYP3A4 and CYP3A5 might play a role in genetic susceptibility to schizophrenia. However, confirmatory studies in independent samples are needed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 5 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2009 Oct 33: 1200-4 |
| PMID | 19591893 |
| Title | A case-control association study between the CYP3A4 and CYP3A5 genes and schizophrenia in the Chinese Han population. |
| Abstract | In this study, variants of two genes coding for cytochrome P450 enzyme (CYP3A4 and CYP3A5) were analysed in a case-control sample using 398 schizophrenic patients and 391 healthy controls. All subjects were unrelated Han Chinese from Shanghai. No difference was observed on the allelic or genotypic distribution of CYP3A4 and CYP3A5 gene polymorphisms between the groups. However, the two-marker haplotypes covering components CYP3A41G and CYP3A53 were observed to be significantly associated with schizophrenia (corrected global p=0.0009). In addition, we identified one common risk haplotype, G/G (present in 59.5% of the general population). The results suggest that CYP3A4 and CYP3A5 might play a role in genetic susceptibility to schizophrenia. However, confirmatory studies in independent samples are needed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 6 | J Clin Psychopharmacol 2009 Jun 29: 272-7 |
| PMID | 19440082 |
| Title | Effects of CYP2D6 and CYP3A5 genotypes on the plasma concentrations of risperidone and 9-hydroxyrisperidone in Korean schizophrenic patients. |
| Abstract | This study was conducted to evaluate the effects of the CYP2D6 and CYP3A5 genotypes on the steady-state plasma levels of risperidone (RIS), 9-hydroxyrisperidone (9-OH-RIS), and the active moiety (RIS plus 9-OH-RIS) in Korean schizophrenic patients. Sixty-four Korean schizophrenic patients were enrolled. CYP2D6 and CYP3A5 genotypes were determined, and the plasma levels of RIS and 9-OH-RIS were measured using high-performance liquid chromatography. The dose-normalized plasma concentrations of RIS, 9-OH-RIS, and the active moiety were compared according to the CYP2D6 and CYP3A5 genotypes. Among the patients, 57 were CYP2D6 extensive metabolizers (EMs; CYP2D6*1/*1, *1/*10, and *10/*10) and 7 were CYP2D6 poor metabolizers (PMs; CYP2D6*1/*5 and *10/*5). For the CYP3A5 genotype, 30 patients were CYP3A5*1 expressors (*1/*1 [n = 1] and *1/*3 [n = 29]) and 34 patients were CYP3A5 nonexpressors (*3/*3). The plasma levels of RIS (2.03 ng/mL per milligram for EMs vs 5.57 ng/mL per milligram for PMs, P < 0.001) and 9-OH-RIS (5.06 ng/mL per milligram for EMs vs 0.22 ng/mL per milligram for PMs, P < 0.001) were significantly different among CYP2D6 genotype groups, but the CYP2D6 EMs (7.09 ng/mL per milligram) and PMs (5.79 ng/mL per milligram) did not show no difference in the levels of the active moiety (P = 0.470). CYP3A5 nonexpressors exhibited higher plasma concentrations of both RIS and 9-OH-RIS than its expressors. In the case of 9-OH-RIS, CYP3A5 nonexpressors exhibited significantly higher concentrations than CYP3A5 expressors (5.42 vs 3.51 ng/mL per milligram, P = 0.022). In addition, concentrations of the active moiety were also significantly different between the CYP3A5 nonexpressors (8.39 ng/mL per milligram) and expressors (5.30 ng/mL per milligram, P = 0.005). In conclusion, both CYP2D6 and CYP3A5 genotypes affected plasma levels of RIS and 9-OH-RIS, whereas the active moiety levels were influenced only by the CYP3A5 genotype but not by the CYP2D6 genotype. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 7 | Pharmacogenomics 2010 Dec 11: 1725-31 |
| PMID | 21142916 |
| Title | Xenobiotic metabolizing and transporter genes: gene-gene interactions in schizophrenia and related disorders. |
| Abstract | In this study we explored possible epistasis between CYP2D6 (*3, *4, *5, *6 and *1xN), CYP3A5 (*3), CYP1A2 (*1C and *1F) and ABCB1 (G2677T) in schizophrenia and related disorders. A total of 344 patients diagnosed with schizophrenia and related disorders, and 484 healthy controls participated in the present study. We analyzed gene-gene interactions by multifactor dimensionality reduction. A four-way model including ABCB1 G2677T, CYP3A5*3, CYP1A2*1F and CYP2D6*4 variants had the best overall performances (accuracy: 0.573) and a crossvalidation consistency of 10/10 (permutation testing p < 0.004). Our results suggest a significant involvement of CYPs and transporters in brain metabolism and homeostasis, and provide evidence of gene-gene interactions among xenobiotic metabolizing and transporter genes in the context of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 8 | Xenobiotica 2010 Nov 40: 721-9 |
| PMID | 20937004 |
| Title | In vitro assessment of metabolic drug?drug interaction potential of AZD2624, neurokinin-3 receptor antagonist, through cytochrome P(450) enzyme identification, inhibition, and induction studies. |
| Abstract | AZD2624 was pharmacologically characterized as a NK3 receptor antagonist intended for treatment of schizophrenia. The metabolic drug-drug interaction potential of AZD2624 was evaluated in in vitro studies. CYP3A4 and CYP3A5 appeared to be the primary enzymes mediating the formation of pharmacologically active ketone metabolite (M1), whereas CYP3A4, CYP3A5, and CYP2C9 appeared to be the enzymes responsible for the formation of the hydroxylated metabolite (M2). The apparent K(m) values were 1.5 and 6.3 µM for the formation of M1 and M2 in human liver microsomes, respectively. AZD2624 exhibited an inhibitory effect on microsomal CYP3A4/5 activities with apparent IC(50) values of 7.1 and 19.8 µM for midazolam and testosterone assays, respectively. No time-dependent inactivation of CYP3A4/5 activity (midazolam 1'-hydroxylation) by AZD2624 was observed. AZD2624 demonstrated weak to no inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. AZD2624 was not an inducer of CYP1A2 or CYP2B6. Although AZD2624-induced CYP3A4 activity in hepatocytes, the potential of AZD2624 to cause inductive drug interactions of this enzyme was low at relevant exposure concentration. Together with targeted low efficacious concentration, the results of this study demonstrated AZD2624 has a relatively low metabolic drug-drug interaction potential towards co-administered drugs. However, metabolism of AZD2624 might be inhibited when co-administrated with potent CYP3A4/5 inhibitors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 9 | Ther Drug Monit 2014 Oct 36: 651-5 |
| PMID | 24682161 |
| Title | Effects of genetic polymorphisms of CYP2D6, CYP3A5, and ABCB1 on the steady-state plasma concentrations of aripiprazole and its active metabolite, dehydroaripiprazole, in Japanese patients with schizophrenia. |
| Abstract | We studied the effects of various factors, including genetic polymorphisms of the cytochrome P450 (CYP) 2D6, CYP3A5, and ABCB1, age, gender, and smoking habit on the steady-state plasma concentrations of aripiprazole and its active metabolite, dehydroaripiprazole, in 89 patients with schizophrenia (46 males, 43 females). All patients had been receiving fixed doses of aripiprazole for at least 2 weeks. The daily doses were 24 mg (n = 56) and 12 mg (n = 33). No other drugs except biperiden and flunitrazepam were coadministered. Plasma concentrations of aripiprazole and dehydroaripiprazole were measured using liquid chromatography with mass-spectrometric detection. The CYP2D6 (CYP2D6*5, CYP2D6*10, and CYP2D6*14), CYP3A5 (CYP3A5*3), and ABCB1 (C3435T and G2677T/A) genotypes were identified by PCR analyses. The mean concentration/dose ratios of aripiprazole and the sum of aripiprazole and dehydroaripiprazole were significantly higher in patients with 1 (P < 0.01 and P < 0.01) or 2 (P < 0.001 and P < 0.05) mutated alleles for CYP2D6 than in those without mutated alleles. No differences were found in the values of dehydroaripiprazole among CYP2D6 genotypes. There were no differences in the values of aripiprazole, dehydroaripiprazole, and the sum of the 2 compounds among CYP3A5 or the 2 ABCB1 variants. Multiple regression analyses including these polymorphisms, age, gender, and smoking habit showed that only the number of mutated alleles for CYP2D6 was correlated with mean concentration/dose ratios of aripiprazole [standardized partial correlation coefficients (beta) = 0.420, P < 0.001] and the sum of the 2 compounds (standardized beta = 0.335, P < 0.01). The findings of this study suggest that CYP2D6 genotypes play an important role in controlling steady-state plasma concentrations of aripiprazole and the sum of aripiprazole and dehydroaripiprazole in Asian subjects, whereas CYP3A5 and ABCB1 genotypes seemed unlikely to have an impact. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 10 | Pharmacogenet. Genomics 2014 Jan 24: 35-42 |
| PMID | 24240480 |
| Title | Influence of ABCB1 and CYP3A5 genetic polymorphisms on the pharmacokinetics of quetiapine in healthy volunteers. |
| Abstract | Quetiapine is an atypical antipsychotic drug used to treat schizophrenia and acute episodes of mania. Quetiapine is metabolized by CYP3A enzymes including CYP3A5 and is a substrate of P-glycoprotein, an efflux drug transporter encoded by the ABCB1 gene. We assessed the effects of ABCB1 [c.1236C>T (rs1128503), c.2677G>T/A (rs2032582), c.3435C>T (rs1045642)] and CYP3A5*3 (6986A>G) (rs776746) polymorphisms on the pharmacokinetics of quetiapine in humans. Forty healthy male individuals were enrolled, and their ABCB1 and CYP3A5 polymorphisms were assessed. After a single dose of 100 mg quetiapine was administered, plasma concentrations of quetiapine were measured for 24 h and pharmacokinetic analysis was carried out. The ABCB1 polymorphisms including c.1236C>T, c.2677G>T/A, and c.3435C>T did not affect plasma levels of quetiapine, and its pharmacokinetic parameters did not differ among ABCB1 genotype groups. However, the CYP3A5*3 polymorphism significantly affected the plasma level of quetiapine and its pharmacokinetics. The peak plasma concentration of quetiapine was 208.39 ng/ml for CYP3A5*1/*1, 243.46 ng/ml for CYP3A5*1/*3, and 332.94 ng/ml for CYP3A5*3/*3 (P=0.0118). The mean AUC(inf) (area under the time vs. concentration curve from 0 to infinity) value was 627.3, 712.77, and 1045.29 ng h/ml, respectively (P=0.0017). The results indicated that the genetic polymorphism of CYP3A5*3 but not ABCB1 significantly influences the plasma level of quetiapine and its pharmacokinetics. These findings suggest that the CYP3A5 genetic polymorphism affects the disposition of quetiapine and provide a plausible explanation for interindividual variation in the disposition of this drug. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |