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.
© 2011 Blackwell Publishing Ltd.