Individual differences in in vitro and in vivo metabolic clearances of antipsychotic risperidone from Japanese subjects genotyped for cytochrome P450 2D6 and 3A5
Objective There are conflicting reports regarding the effects of cytochrome P450 (P450, CYP) genotypes on the plasma concentrations of risperidone and its pharmacologically active metabolite, 9‐hydroxyrisperidone (paliperidone), in clinical patients. The aim of this study was to investigate individu...
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| Published in | Human psychopharmacology Vol. 31; no. 2; pp. 93 - 102 |
|---|---|
| Main Authors | , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
England
Blackwell Publishing Ltd
01.03.2016
Wiley Subscription Services, Inc |
| Subjects | |
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| Abstract | Objective
There are conflicting reports regarding the effects of cytochrome P450 (P450, CYP) genotypes on the plasma concentrations of risperidone and its pharmacologically active metabolite, 9‐hydroxyrisperidone (paliperidone), in clinical patients. The aim of this study was to investigate individual differences in the metabolic clearance of risperidone in vitro and in vivo.
Methods
In vitro liver microsomal risperidone 9‐hydroxylation activities and in vivo plasma concentrations of risperidone and paliperidone were investigated in 15 male and 12 female Japanese subjects (mean age 52 years, range: 24–75 years) genotyped for CYP2D6 and CYP3A5.
Results
CYP2D6 intermediate and poor metabolizers showed significantly lower liver microsomal risperidone 9‐hydroxylation activities than extensive metabolizers did at 5 μM of risperidone; this difference was not evident at 50 μM of risperidone. The recombinant CYP3A5 Vmax/Km value for risperidone 9‐hydroxylation was 30% that of CYP3A4, and liver microsomes from CYP3A5 expressers had similar risperidone 9‐hydroxylation activities to those of CYP3A5 poor expressers. The plasma concentration/dose ratios for risperidone and paliperidone in 27 Japanese patients were not significantly influenced by the CYP2D6 or CYP3A5 genotypes.
Conclusions
Individual differences in metabolic clearance of risperidone under the present conditions were not significantly influenced by the genotypes of CYP2D6 or CYP3A5. Copyright © 2016 John Wiley & Sons, Ltd. |
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| AbstractList | There are conflicting reports regarding the effects of cytochrome P450 (P450, CYP) genotypes on the plasma concentrations of risperidone and its pharmacologically active metabolite, 9-hydroxyrisperidone (paliperidone), in clinical patients. The aim of this study was to investigate individual differences in the metabolic clearance of risperidone in vitro and in vivo.OBJECTIVEThere are conflicting reports regarding the effects of cytochrome P450 (P450, CYP) genotypes on the plasma concentrations of risperidone and its pharmacologically active metabolite, 9-hydroxyrisperidone (paliperidone), in clinical patients. The aim of this study was to investigate individual differences in the metabolic clearance of risperidone in vitro and in vivo.In vitro liver microsomal risperidone 9-hydroxylation activities and in vivo plasma concentrations of risperidone and paliperidone were investigated in 15 male and 12 female Japanese subjects (mean age 52 years, range: 24-75 years) genotyped for CYP2D6 and CYP3A5.METHODSIn vitro liver microsomal risperidone 9-hydroxylation activities and in vivo plasma concentrations of risperidone and paliperidone were investigated in 15 male and 12 female Japanese subjects (mean age 52 years, range: 24-75 years) genotyped for CYP2D6 and CYP3A5.CYP2D6 intermediate and poor metabolizers showed significantly lower liver microsomal risperidone 9-hydroxylation activities than extensive metabolizers did at 5 μM of risperidone; this difference was not evident at 50 μM of risperidone. The recombinant CYP3A5 Vmax/Km value for risperidone 9-hydroxylation was 30% that of CYP3A4, and liver microsomes from CYP3A5 expressers had similar risperidone 9-hydroxylation activities to those of CYP3A5 poor expressers. The plasma concentration/dose ratios for risperidone and paliperidone in 27 Japanese patients were not significantly influenced by the CYP2D6 or CYP3A5 genotypes.RESULTSCYP2D6 intermediate and poor metabolizers showed significantly lower liver microsomal risperidone 9-hydroxylation activities than extensive metabolizers did at 5 μM of risperidone; this difference was not evident at 50 μM of risperidone. The recombinant CYP3A5 Vmax/Km value for risperidone 9-hydroxylation was 30% that of CYP3A4, and liver microsomes from CYP3A5 expressers had similar risperidone 9-hydroxylation activities to those of CYP3A5 poor expressers. The plasma concentration/dose ratios for risperidone and paliperidone in 27 Japanese patients were not significantly influenced by the CYP2D6 or CYP3A5 genotypes.Individual differences in metabolic clearance of risperidone under the present conditions were not significantly influenced by the genotypes of CYP2D6 or CYP3A5.CONCLUSIONSIndividual differences in metabolic clearance of risperidone under the present conditions were not significantly influenced by the genotypes of CYP2D6 or CYP3A5. Objective There are conflicting reports regarding the effects of cytochrome P450 (P450, CYP) genotypes on the plasma concentrations of risperidone and its pharmacologically active metabolite, 9-hydroxyrisperidone (paliperidone), in clinical patients. The aim of this study was to investigate individual differences in the metabolic clearance of risperidone in vitro and in vivo. Methods In vitro liver microsomal risperidone 9-hydroxylation activities and in vivo plasma concentrations of risperidone and paliperidone were investigated in 15 male and 12 female Japanese subjects (mean age 52years, range: 24-75years) genotyped for CYP2D6 and CYP3A5. Results CYP2D6 intermediate and poor metabolizers showed significantly lower liver microsomal risperidone 9-hydroxylation activities than extensive metabolizers did at 5µM of risperidone; this difference was not evident at 50µM of risperidone. The recombinant CYP3A5 Vmax/Km value for risperidone 9-hydroxylation was 30% that of CYP3A4, and liver microsomes from CYP3A5 expressers had similar risperidone 9-hydroxylation activities to those of CYP3A5 poor expressers. The plasma concentration/dose ratios for risperidone and paliperidone in 27 Japanese patients were not significantly influenced by the CYP2D6 or CYP3A5 genotypes. Conclusions Individual differences in metabolic clearance of risperidone under the present conditions were not significantly influenced by the genotypes of CYP2D6 or CYP3A5. Copyright © 2016 John Wiley & Sons, Ltd. There are conflicting reports regarding the effects of cytochrome P450 (P450, CYP) genotypes on the plasma concentrations of risperidone and its pharmacologically active metabolite, 9-hydroxyrisperidone (paliperidone), in clinical patients. The aim of this study was to investigate individual differences in the metabolic clearance of risperidone in vitro and in vivo. In vitro liver microsomal risperidone 9-hydroxylation activities and in vivo plasma concentrations of risperidone and paliperidone were investigated in 15 male and 12 female Japanese subjects (mean age 52 years, range: 24-75 years) genotyped for CYP2D6 and CYP3A5. CYP2D6 intermediate and poor metabolizers showed significantly lower liver microsomal risperidone 9-hydroxylation activities than extensive metabolizers did at 5 μM of risperidone; this difference was not evident at 50 μM of risperidone. The recombinant CYP3A5 Vmax/Km value for risperidone 9-hydroxylation was 30% that of CYP3A4, and liver microsomes from CYP3A5 expressers had similar risperidone 9-hydroxylation activities to those of CYP3A5 poor expressers. The plasma concentration/dose ratios for risperidone and paliperidone in 27 Japanese patients were not significantly influenced by the CYP2D6 or CYP3A5 genotypes. Individual differences in metabolic clearance of risperidone under the present conditions were not significantly influenced by the genotypes of CYP2D6 or CYP3A5. Objective There are conflicting reports regarding the effects of cytochrome P450 (P450, CYP) genotypes on the plasma concentrations of risperidone and its pharmacologically active metabolite, 9-hydroxyrisperidone (paliperidone), in clinical patients. The aim of this study was to investigate individual differences in the metabolic clearance of risperidone in vitro and in vivo. Methods In vitro liver microsomal risperidone 9-hydroxylation activities and in vivo plasma concentrations of risperidone and paliperidone were investigated in 15 male and 12 female Japanese subjects (mean age 52years, range: 24-75years) genotyped for CYP2D6 and CYP3A5. Results CYP2D6 intermediate and poor metabolizers showed significantly lower liver microsomal risperidone 9-hydroxylation activities than extensive metabolizers did at 5 mu M of risperidone; this difference was not evident at 50 mu M of risperidone. The recombinant CYP3A5 V sub(max)/K sub(m) value for risperidone 9-hydroxylation was 30% that of CYP3A4, and liver microsomes from CYP3A5 expressers had similar risperidone 9-hydroxylation activities to those of CYP3A5 poor expressers. The plasma concentration/dose ratios for risperidone and paliperidone in 27 Japanese patients were not significantly influenced by the CYP2D6 or CYP3A5 genotypes. Conclusions Individual differences in metabolic clearance of risperidone under the present conditions were not significantly influenced by the genotypes of CYP2D6 or CYP3A5. Objective There are conflicting reports regarding the effects of cytochrome P450 (P450, CYP) genotypes on the plasma concentrations of risperidone and its pharmacologically active metabolite, 9‐hydroxyrisperidone (paliperidone), in clinical patients. The aim of this study was to investigate individual differences in the metabolic clearance of risperidone in vitro and in vivo. Methods In vitro liver microsomal risperidone 9‐hydroxylation activities and in vivo plasma concentrations of risperidone and paliperidone were investigated in 15 male and 12 female Japanese subjects (mean age 52 years, range: 24–75 years) genotyped for CYP2D6 and CYP3A5. Results CYP2D6 intermediate and poor metabolizers showed significantly lower liver microsomal risperidone 9‐hydroxylation activities than extensive metabolizers did at 5 μM of risperidone; this difference was not evident at 50 μM of risperidone. The recombinant CYP3A5 Vmax/Km value for risperidone 9‐hydroxylation was 30% that of CYP3A4, and liver microsomes from CYP3A5 expressers had similar risperidone 9‐hydroxylation activities to those of CYP3A5 poor expressers. The plasma concentration/dose ratios for risperidone and paliperidone in 27 Japanese patients were not significantly influenced by the CYP2D6 or CYP3A5 genotypes. Conclusions Individual differences in metabolic clearance of risperidone under the present conditions were not significantly influenced by the genotypes of CYP2D6 or CYP3A5. Copyright © 2016 John Wiley & Sons, Ltd. |
| Author | Goto, Akiko Yamazaki, Hiroshi Okubo, Maho Murayama, Norie Akimoto, Youichi Morita, Shoko |
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| Keywords | clearance paliperidone CYP2D6 CYP3A5 Japanese risperidone |
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There are conflicting reports regarding the effects of cytochrome P450 (P450, CYP) genotypes on the plasma concentrations of risperidone and its... There are conflicting reports regarding the effects of cytochrome P450 (P450, CYP) genotypes on the plasma concentrations of risperidone and its... Objective There are conflicting reports regarding the effects of cytochrome P450 (P450, CYP) genotypes on the plasma concentrations of risperidone and its... |
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| SubjectTerms | Adult Aged Antipsychotic Agents - pharmacokinetics Antipsychotic Agents - therapeutic use Asian Continental Ancestry Group - genetics clearance CYP2D6 CYP3A5 Cytochrome P-450 CYP1A2 - metabolism Cytochrome P-450 CYP2D6 - genetics Cytochrome P-450 CYP2D6 - metabolism Cytochrome P-450 CYP3A - genetics Cytochrome P-450 CYP3A - metabolism Dose-Response Relationship, Drug Female Genotyping Techniques Humans Japan Japanese Male Microsomes, Liver - drug effects Microsomes, Liver - enzymology Middle Aged paliperidone Recombinant Proteins - metabolism risperidone Risperidone - pharmacokinetics Risperidone - therapeutic use Smoking - genetics Smoking - metabolism Young Adult |
| Title | Individual differences in in vitro and in vivo metabolic clearances of antipsychotic risperidone from Japanese subjects genotyped for cytochrome P450 2D6 and 3A5 |
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