Cytochrome P450 3A inhibitor itraconazole affects plasma concentrations of risperidone and 9-hydroxyrisperidone in schizophrenic patients

Sun Min Jung, Kyoung Ah Kim, Hyun Kee Cho, Il Geun Jung, Pil Whan Park, Won Tan Byun, Ji-Young Park

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Background and Objective: Despite the belief that cytochrome P450 (CYP) 2D6 alone is responsible for the metabolism of risperidone, several studies suggest that CYP3A may be involved. The aim of this study was to evaluate the effect of itraconazole, a CYP3A inhibitor, on the plasma concentrations of risperidone and 9-hydroxyrisperidone in schizophrenic patients in relation to CYP2D6 genotype. Methods: Nineteen schizophrenic patients treated with 2 to 8 mg/d of risperidone received 200 mg/d of itraconazole for a week. Plasma concentrations of risperidone and 9-hydroxyrisperidone were measured immediately before and after itraconazole treatment, as well as at 1 week after itraconazole treatment was stopped, together with clinical assessment by use of the Udvalg for Kliniske Undersøgelser Side Effect Rating Scale and the Brief Psychiatric Rating Scale. Results: Dose-normalized plasma concentrations of risperidone and 9-hydroxyrisperidone before itraconazole treatment (0.9 ± 0.8 ng·mL-1·mg-1 and 6.9 ± 3.3 ng·mL-1·mg-1, respectively) were significantly elevated after itraconazole treatment (1.6 ± 1.3 ng·mL-1·mg-1 and 11.3 ± 4.5 ng·mL-1·mg-1) and decreased 1 week after its discontinuation (1.0 ± 0.8 ng·mL-1·mg -1 and 7.2 ± 3.7 ng·mL-1·mg -1) (P < .01). However, the ratio of risperidone/9- hydroxyrisperidone, an index of CYP2D6 activity, did not differ before itraconazole treatment (0.14 ± 0.13), after itraconazole treatment (0.15 ± 0.13), and 1 week after discontinuation (0.14 ± 0.13) (P > .05). Itraconazole increased the concentrations of risperidone by 69% (P < .001) and 75% (P < .01) in CYP2D6 extensive and poor metabolizers, respectively. In addition, the active moiety (risperidone plus 9-hydroxyrisperidone) also increased similarly, by 71% (P < .001) and 73% (P < .05), respectively, with itraconazole, without a significant difference between CYP2D6 genotypes. The scores on the Brief Psychiatric Rating Scale decreased significantly but only by 6% after itraconazole treatment (P < .05); however, the scores on the Udvalg for Kliniske Undersøgelser Side Effect Rating Scale were not changed. Conclusions: Our results provide in vivo evidence of the involvement of CYP3A in the disposition of risperidone and 9-hydroxyrisperidone. In addition to CYP2D6, treatment with CYP3A inhibitor(s) including itraconazole may influence clinical symptoms and risperidone side effects.

Original languageEnglish
Pages (from-to)520-528
Number of pages9
JournalClinical Pharmacology and Therapeutics
Volume78
Issue number5
DOIs
Publication statusPublished - 2005 Nov 1
Externally publishedYes

Fingerprint

Cytochrome P-450 CYP3A
Itraconazole
Risperidone
Cytochrome P-450 CYP2D6
Brief Psychiatric Rating Scale
Genotype
Paliperidone Palmitate
Therapeutics

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Cytochrome P450 3A inhibitor itraconazole affects plasma concentrations of risperidone and 9-hydroxyrisperidone in schizophrenic patients. / Jung, Sun Min; Kim, Kyoung Ah; Cho, Hyun Kee; Jung, Il Geun; Park, Pil Whan; Byun, Won Tan; Park, Ji-Young.

In: Clinical Pharmacology and Therapeutics, Vol. 78, No. 5, 01.11.2005, p. 520-528.

Research output: Contribution to journalArticle

Jung, Sun Min ; Kim, Kyoung Ah ; Cho, Hyun Kee ; Jung, Il Geun ; Park, Pil Whan ; Byun, Won Tan ; Park, Ji-Young. / Cytochrome P450 3A inhibitor itraconazole affects plasma concentrations of risperidone and 9-hydroxyrisperidone in schizophrenic patients. In: Clinical Pharmacology and Therapeutics. 2005 ; Vol. 78, No. 5. pp. 520-528.
@article{ff0e2b6cf7814b9ea5368ba1a6e2f23b,
title = "Cytochrome P450 3A inhibitor itraconazole affects plasma concentrations of risperidone and 9-hydroxyrisperidone in schizophrenic patients",
abstract = "Background and Objective: Despite the belief that cytochrome P450 (CYP) 2D6 alone is responsible for the metabolism of risperidone, several studies suggest that CYP3A may be involved. The aim of this study was to evaluate the effect of itraconazole, a CYP3A inhibitor, on the plasma concentrations of risperidone and 9-hydroxyrisperidone in schizophrenic patients in relation to CYP2D6 genotype. Methods: Nineteen schizophrenic patients treated with 2 to 8 mg/d of risperidone received 200 mg/d of itraconazole for a week. Plasma concentrations of risperidone and 9-hydroxyrisperidone were measured immediately before and after itraconazole treatment, as well as at 1 week after itraconazole treatment was stopped, together with clinical assessment by use of the Udvalg for Kliniske Unders{\o}gelser Side Effect Rating Scale and the Brief Psychiatric Rating Scale. Results: Dose-normalized plasma concentrations of risperidone and 9-hydroxyrisperidone before itraconazole treatment (0.9 ± 0.8 ng·mL-1·mg-1 and 6.9 ± 3.3 ng·mL-1·mg-1, respectively) were significantly elevated after itraconazole treatment (1.6 ± 1.3 ng·mL-1·mg-1 and 11.3 ± 4.5 ng·mL-1·mg-1) and decreased 1 week after its discontinuation (1.0 ± 0.8 ng·mL-1·mg -1 and 7.2 ± 3.7 ng·mL-1·mg -1) (P < .01). However, the ratio of risperidone/9- hydroxyrisperidone, an index of CYP2D6 activity, did not differ before itraconazole treatment (0.14 ± 0.13), after itraconazole treatment (0.15 ± 0.13), and 1 week after discontinuation (0.14 ± 0.13) (P > .05). Itraconazole increased the concentrations of risperidone by 69{\%} (P < .001) and 75{\%} (P < .01) in CYP2D6 extensive and poor metabolizers, respectively. In addition, the active moiety (risperidone plus 9-hydroxyrisperidone) also increased similarly, by 71{\%} (P < .001) and 73{\%} (P < .05), respectively, with itraconazole, without a significant difference between CYP2D6 genotypes. The scores on the Brief Psychiatric Rating Scale decreased significantly but only by 6{\%} after itraconazole treatment (P < .05); however, the scores on the Udvalg for Kliniske Unders{\o}gelser Side Effect Rating Scale were not changed. Conclusions: Our results provide in vivo evidence of the involvement of CYP3A in the disposition of risperidone and 9-hydroxyrisperidone. In addition to CYP2D6, treatment with CYP3A inhibitor(s) including itraconazole may influence clinical symptoms and risperidone side effects.",
author = "Jung, {Sun Min} and Kim, {Kyoung Ah} and Cho, {Hyun Kee} and Jung, {Il Geun} and Park, {Pil Whan} and Byun, {Won Tan} and Ji-Young Park",
year = "2005",
month = "11",
day = "1",
doi = "10.1016/j.clpt.2005.07.007",
language = "English",
volume = "78",
pages = "520--528",
journal = "Clinical Pharmacology and Therapeutics",
issn = "0009-9236",
publisher = "Nature Publishing Group",
number = "5",

}

TY - JOUR

T1 - Cytochrome P450 3A inhibitor itraconazole affects plasma concentrations of risperidone and 9-hydroxyrisperidone in schizophrenic patients

AU - Jung, Sun Min

AU - Kim, Kyoung Ah

AU - Cho, Hyun Kee

AU - Jung, Il Geun

AU - Park, Pil Whan

AU - Byun, Won Tan

AU - Park, Ji-Young

PY - 2005/11/1

Y1 - 2005/11/1

N2 - Background and Objective: Despite the belief that cytochrome P450 (CYP) 2D6 alone is responsible for the metabolism of risperidone, several studies suggest that CYP3A may be involved. The aim of this study was to evaluate the effect of itraconazole, a CYP3A inhibitor, on the plasma concentrations of risperidone and 9-hydroxyrisperidone in schizophrenic patients in relation to CYP2D6 genotype. Methods: Nineteen schizophrenic patients treated with 2 to 8 mg/d of risperidone received 200 mg/d of itraconazole for a week. Plasma concentrations of risperidone and 9-hydroxyrisperidone were measured immediately before and after itraconazole treatment, as well as at 1 week after itraconazole treatment was stopped, together with clinical assessment by use of the Udvalg for Kliniske Undersøgelser Side Effect Rating Scale and the Brief Psychiatric Rating Scale. Results: Dose-normalized plasma concentrations of risperidone and 9-hydroxyrisperidone before itraconazole treatment (0.9 ± 0.8 ng·mL-1·mg-1 and 6.9 ± 3.3 ng·mL-1·mg-1, respectively) were significantly elevated after itraconazole treatment (1.6 ± 1.3 ng·mL-1·mg-1 and 11.3 ± 4.5 ng·mL-1·mg-1) and decreased 1 week after its discontinuation (1.0 ± 0.8 ng·mL-1·mg -1 and 7.2 ± 3.7 ng·mL-1·mg -1) (P < .01). However, the ratio of risperidone/9- hydroxyrisperidone, an index of CYP2D6 activity, did not differ before itraconazole treatment (0.14 ± 0.13), after itraconazole treatment (0.15 ± 0.13), and 1 week after discontinuation (0.14 ± 0.13) (P > .05). Itraconazole increased the concentrations of risperidone by 69% (P < .001) and 75% (P < .01) in CYP2D6 extensive and poor metabolizers, respectively. In addition, the active moiety (risperidone plus 9-hydroxyrisperidone) also increased similarly, by 71% (P < .001) and 73% (P < .05), respectively, with itraconazole, without a significant difference between CYP2D6 genotypes. The scores on the Brief Psychiatric Rating Scale decreased significantly but only by 6% after itraconazole treatment (P < .05); however, the scores on the Udvalg for Kliniske Undersøgelser Side Effect Rating Scale were not changed. Conclusions: Our results provide in vivo evidence of the involvement of CYP3A in the disposition of risperidone and 9-hydroxyrisperidone. In addition to CYP2D6, treatment with CYP3A inhibitor(s) including itraconazole may influence clinical symptoms and risperidone side effects.

AB - Background and Objective: Despite the belief that cytochrome P450 (CYP) 2D6 alone is responsible for the metabolism of risperidone, several studies suggest that CYP3A may be involved. The aim of this study was to evaluate the effect of itraconazole, a CYP3A inhibitor, on the plasma concentrations of risperidone and 9-hydroxyrisperidone in schizophrenic patients in relation to CYP2D6 genotype. Methods: Nineteen schizophrenic patients treated with 2 to 8 mg/d of risperidone received 200 mg/d of itraconazole for a week. Plasma concentrations of risperidone and 9-hydroxyrisperidone were measured immediately before and after itraconazole treatment, as well as at 1 week after itraconazole treatment was stopped, together with clinical assessment by use of the Udvalg for Kliniske Undersøgelser Side Effect Rating Scale and the Brief Psychiatric Rating Scale. Results: Dose-normalized plasma concentrations of risperidone and 9-hydroxyrisperidone before itraconazole treatment (0.9 ± 0.8 ng·mL-1·mg-1 and 6.9 ± 3.3 ng·mL-1·mg-1, respectively) were significantly elevated after itraconazole treatment (1.6 ± 1.3 ng·mL-1·mg-1 and 11.3 ± 4.5 ng·mL-1·mg-1) and decreased 1 week after its discontinuation (1.0 ± 0.8 ng·mL-1·mg -1 and 7.2 ± 3.7 ng·mL-1·mg -1) (P < .01). However, the ratio of risperidone/9- hydroxyrisperidone, an index of CYP2D6 activity, did not differ before itraconazole treatment (0.14 ± 0.13), after itraconazole treatment (0.15 ± 0.13), and 1 week after discontinuation (0.14 ± 0.13) (P > .05). Itraconazole increased the concentrations of risperidone by 69% (P < .001) and 75% (P < .01) in CYP2D6 extensive and poor metabolizers, respectively. In addition, the active moiety (risperidone plus 9-hydroxyrisperidone) also increased similarly, by 71% (P < .001) and 73% (P < .05), respectively, with itraconazole, without a significant difference between CYP2D6 genotypes. The scores on the Brief Psychiatric Rating Scale decreased significantly but only by 6% after itraconazole treatment (P < .05); however, the scores on the Udvalg for Kliniske Undersøgelser Side Effect Rating Scale were not changed. Conclusions: Our results provide in vivo evidence of the involvement of CYP3A in the disposition of risperidone and 9-hydroxyrisperidone. In addition to CYP2D6, treatment with CYP3A inhibitor(s) including itraconazole may influence clinical symptoms and risperidone side effects.

UR - http://www.scopus.com/inward/record.url?scp=28144455896&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=28144455896&partnerID=8YFLogxK

U2 - 10.1016/j.clpt.2005.07.007

DO - 10.1016/j.clpt.2005.07.007

M3 - Article

VL - 78

SP - 520

EP - 528

JO - Clinical Pharmacology and Therapeutics

JF - Clinical Pharmacology and Therapeutics

SN - 0009-9236

IS - 5

ER -