title: Effect of cytochrome P450 3A4 inhibitor ketoconazole on risperidone pharmacokinetics in healthy volunteers.
abstract: 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.
  
  
  CONCLUSIONS
  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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Pharmacology, Faculty of Science, Prince of Songkla University, Thailand. werawath.m@gmail.com
authors.forename: W
authors.initials: W
authors.lastname: Mahatthanatrakul
authors.forename: S
authors.initials: S
authors.lastname: Sriwiriyajan
authors.forename: W
authors.initials: W
authors.lastname: Ridtitid
authors.forename: J
authors.initials: J
authors.lastname: Boonleang
authors.forename: M
authors.initials: M
authors.lastname: Wongnawa
authors.forename: N
authors.initials: N
authors.lastname: Rujimamahasan
authors.forename: W
authors.initials: W
authors.lastname: Pipatrattanaseree
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D007555:Isoxazoles / Q000493:pharmacokinetics; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D000068882:Paliperidone Palmitate; D011743:Pyrimidines / Q000493:pharmacokinetics; D018967:Risperidone / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D007555:Isoxazoles; D011743:Pyrimidines; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D018967:Risperidone; D000068882:Paliperidone Palmitate; D007654:Ketoconazole