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Thai J Pharmacol Vol. 31, No.1, 2009 Original article
P03
Effect of Ketoconazole on the Pharmacokinetics of Risperidone
in Healthy Thai Male Volunteers
Werawath Mahatthanatrakul1*,Nachanada Rujimamahasan1*, Wibool Ridtitid1,Mlinee Wongnawa1, Somchai Sriwiriyajan1 ,Jutima Boonliang2 ,Weerachai Pipatrattanaseree2 1Department of Pharmacology, Faculty of Science, 2Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Songkhla, Thailand E-mail: werawatthana.m@psu.ac.th Abstract
Risperidone , a psychotropic agent, is mainly used to treat schizophrenia. The main metabolic pathway is through hydroxylation of risperidone to 9- hydroxyrisperidone by the enzyme CYP 2D6 and to a lesser extent , CYP 3A4. Ketoconazole is an oral antifungal agent of the imidazole class, Ketoconazole is a potent inhibitor of CYP 3A4 activity that can increase plasma concentrations of various drugs , when concomitantly administered during treatment. Therefore, ketoconazole may alter the pharmacokinetics of risperidone when these drugs are coadministered. The objective of this study is to examine the effect of risperidone on the pharmacokinetics of a single oral dose of risperidone in healthy volunteers In the present study, the pharmacokinetics parameters of risperidone were determined in 10 healthy male volunteers. An open, randomized, two phases crossover design was used in this study. In phases 1, each subject ingested a single dose of 2 mg risperidone alone and in phase 2 , each subject ingested the same dose of risperidone after pretreatment with 200 mg of given orally ketoconazole once daily for 3 days. Plasma concentrations of risperidone at specific times (0,15,30,45 min and1,1.5,2,3,4,5,6,8,12,24,48,72,96 hr ) were determined by LC-MS/MS method. The results may be showed that ketoconazole significantly increase the mean C max, Tmax ,T1/2,AUC0-48 , AUC0-α,Vd and Cl of risperidone In conclusion, the alteration in the risperidone pharmacokinetics parameters may be due to inhibition of CYP 3A4 . Therefore, clinicians should be careful for increasing the dose of risperidone if the patient receives risperidone coadministered with ketoconazole , the dose of risperidone should be adjusted to maximize the therapeutic efficacy and reduce the cost of the therapy. If it possible, ketoconazole should not be coadminitered with risperidone to maximize the therapeutic efficacy of risperidone Keywords: risperidone, ketoconazole, CYP3A4
Introduction
As ketoconazole is one of azole compounds, a number of side effects are associated with ketoconazole as a result of inhibition of these mammalian enzymes (Venkatakrishnan, 2000). Ketoconazole can inhibit CYP3A4, the major CYP isoform of the liver (Suzuki, 2000). The inhibitions of CYP3A4 results in drug-drug interactions involving ketoconazole can decrease the rate of clearance of many drugs.Since risperidone is metabolized by CYP3A4(Lim YP et al.,2009)and this enzyme is also involved in the metabolism of several other drugs ( such as alprazolam, atorvastatin, carbamazepine, cyclosporine,

Source: http://www.thaipharmacol.org/images/stories/article/2009/v31n1p49.pdf