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Effect of cytochrome P450 3A4 inhibitor ketoconazole on risperidone pharmacokinetics in healthy volunteers.
J Clin Pharm Ther. 2012 Apr; 37(2):221-5.JC

Abstract

WHAT IS KNOWN AND OBJECTIVE

Risperidone is an atypical antipsychotic agent used for the treatment of schizophrenia. It is mainly metabolized by human cytochrome P450 CYP2D6 and partly by CYP3A4 to 9-hydroxyrisperidone. Ketoconazole is used as a CYP3A4 inhibitor probe for studying drug-drug interactions. We aim to investigate the effect of ketoconazole on the pharmacokinetics of risperidone in healthy male volunteers.

METHODS

An open-label, randomized, two-phase crossover design with a 2-week washout period was performed in 10 healthy male volunteers. The volunteers received a single oral dose of 2mg of risperidone alone or in combination with 200mg of ketoconazole, once daily for 3days. Serial blood samples were collected at specific periods after ingestion of risperidone for a period of 96h. Plasma concentrations of risperidone and 9-hydroxyrisperidone were determined using a validated HPLC-tandem mass spectrometry method.

RESULTS AND DISCUSSION

After pretreatment with ketoconazole, the clearance of risperidone decreased significantly by 34·81±5·10% and the T(1/2) of risperidone increased significantly by 28·03±40·60%. The AUC(0-96) and AUC(0-∞) of risperidone increased significantly by 66·61± 43·03% and 66·54±39·76%, respectively. The Vd/f of risperidone increased significantly by 39·79±53·59%. However, the C(max) and T(max) of risperidone were not significantly changed, indicating that ketoconazole had minimal effect on the absorption of risperidone. The C(max) , T(max) and T(1/2) of 9-hydroxyrisperidone did not decrease significantly. However, the Cl/f of 9-hydroxyrisperidone increased significantly by 135·07± 124·68%, and the Vd/f of 9-hydroxyrisperidone decreased significantly by 29·47±54·64%. These changes led to a corresponding significant decrease in the AUC(0-96) and AUC(0-∞) of 9-hydroxyrisperidone by 47·76±22·39% and 48·49± 20·03%, respectively. Ketoconazole significantly inhibited the metabolism of risperidone through the inhibition of hepatic CYP3A4. our results suggest that besides CYP2D6, CYP3A4 contributes significantly to the metabolism of risperidone.

WHAT IS NEW AND CONCLUSION

The pharmacokinetics of risperidone was affected by the concomitant administration of ketoconazole. If a CYP3A4 inhibitor is used concomitantly with risperidone, it is necessary for the clinicians to monitor their patients for signs of adverse drug reactions.

Authors+Show Affiliations

Department of Pharmacology, Faculty of Science, Prince of Songkla University, Thailand. werawath.m@gmail.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21518375

Citation

Mahatthanatrakul, W, et al. "Effect of Cytochrome P450 3A4 Inhibitor Ketoconazole On Risperidone Pharmacokinetics in Healthy Volunteers." Journal of Clinical Pharmacy and Therapeutics, vol. 37, no. 2, 2012, pp. 221-5.
Mahatthanatrakul W, Sriwiriyajan S, Ridtitid W, et al. Effect of cytochrome P450 3A4 inhibitor ketoconazole on risperidone pharmacokinetics in healthy volunteers. J Clin Pharm Ther. 2012;37(2):221-5.
Mahatthanatrakul, W., Sriwiriyajan, S., Ridtitid, W., Boonleang, J., Wongnawa, M., Rujimamahasan, N., & Pipatrattanaseree, W. (2012). Effect of cytochrome P450 3A4 inhibitor ketoconazole on risperidone pharmacokinetics in healthy volunteers. Journal of Clinical Pharmacy and Therapeutics, 37(2), 221-5. https://doi.org/10.1111/j.1365-2710.2011.01271.x
Mahatthanatrakul W, et al. Effect of Cytochrome P450 3A4 Inhibitor Ketoconazole On Risperidone Pharmacokinetics in Healthy Volunteers. J Clin Pharm Ther. 2012;37(2):221-5. PubMed PMID: 21518375.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of cytochrome P450 3A4 inhibitor ketoconazole on risperidone pharmacokinetics in healthy volunteers. AU - Mahatthanatrakul,W, AU - Sriwiriyajan,S, AU - Ridtitid,W, AU - Boonleang,J, AU - Wongnawa,M, AU - Rujimamahasan,N, AU - Pipatrattanaseree,W, Y1 - 2011/04/26/ PY - 2011/4/27/entrez PY - 2011/4/27/pubmed PY - 2012/6/26/medline SP - 221 EP - 5 JF - Journal of clinical pharmacy and therapeutics JO - J Clin Pharm Ther VL - 37 IS - 2 N2 - WHAT IS KNOWN AND OBJECTIVE: Risperidone is an atypical antipsychotic agent used for the treatment of schizophrenia. It is mainly metabolized by human cytochrome P450 CYP2D6 and partly by CYP3A4 to 9-hydroxyrisperidone. Ketoconazole is used as a CYP3A4 inhibitor probe for studying drug-drug interactions. We aim to investigate the effect of ketoconazole on the pharmacokinetics of risperidone in healthy male volunteers. METHODS: An open-label, randomized, two-phase crossover design with a 2-week washout period was performed in 10 healthy male volunteers. The volunteers received a single oral dose of 2mg of risperidone alone or in combination with 200mg of ketoconazole, once daily for 3days. Serial blood samples were collected at specific periods after ingestion of risperidone for a period of 96h. Plasma concentrations of risperidone and 9-hydroxyrisperidone were determined using a validated HPLC-tandem mass spectrometry method. RESULTS AND DISCUSSION: After pretreatment with ketoconazole, the clearance of risperidone decreased significantly by 34·81±5·10% and the T(1/2) of risperidone increased significantly by 28·03±40·60%. The AUC(0-96) and AUC(0-∞) of risperidone increased significantly by 66·61± 43·03% and 66·54±39·76%, respectively. The Vd/f of risperidone increased significantly by 39·79±53·59%. However, the C(max) and T(max) of risperidone were not significantly changed, indicating that ketoconazole had minimal effect on the absorption of risperidone. The C(max) , T(max) and T(1/2) of 9-hydroxyrisperidone did not decrease significantly. However, the Cl/f of 9-hydroxyrisperidone increased significantly by 135·07± 124·68%, and the Vd/f of 9-hydroxyrisperidone decreased significantly by 29·47±54·64%. These changes led to a corresponding significant decrease in the AUC(0-96) and AUC(0-∞) of 9-hydroxyrisperidone by 47·76±22·39% and 48·49± 20·03%, respectively. Ketoconazole significantly inhibited the metabolism of risperidone through the inhibition of hepatic CYP3A4. our results suggest that besides CYP2D6, CYP3A4 contributes significantly to the metabolism of risperidone. WHAT IS NEW AND CONCLUSION: The pharmacokinetics of risperidone was affected by the concomitant administration of ketoconazole. If a CYP3A4 inhibitor is used concomitantly with risperidone, it is necessary for the clinicians to monitor their patients for signs of adverse drug reactions. SN - 1365-2710 UR - https://www.unboundmedicine.com/medline/citation/21518375/Effect_of_cytochrome_P450_3A4_inhibitor_ketoconazole_on_risperidone_pharmacokinetics_in_healthy_volunteers_ L2 - https://doi.org/10.1111/j.1365-2710.2011.01271.x DB - PRIME DP - Unbound Medicine ER -