The effects of probenecid on the disposition of risperidone and olanzapine in healthy volunteers

Study Design The metabolic pathways of most xenobiotics and endogenous compounds can be divided into phase 1 (oxidative, reductive, and hydrolytic) and phase 2 (glucuronidation, sulfate conjugation, glycine and glutathione conjugation, and acetylation and methylation) processes. Oxidative metabolism by the cytochrome P450 system has been intensively investigated compared with glucuronidation and other conjugation pathways. The primary aim of this study was to evaluate the disposition of olanzapine or risperidone in healthy volunteers with and without coadministration of the uridine diphosphoglucuronate–glucuronosyltransferase inhibitor probenecid. We hypothesized that olanzapine disposition would be altered as a result of decreased glucuronidation, whereas risperidone disposition would be relatively unaffected. Methods Our objective was to investigate whether this interaction would occur in 12 healthy volunteers, aged 22 to 42 years, who participated in a single‐dose, randomized, 4‐period, double‐blind, crossover study receiving a single dose of either 5 mg olanzapine or 1 mg risperidone with and without 500 mg probenecid (8 doses over 4 days). Multiple blood samples were analyzed by means of liquid chromatography–tandem mass spectrometry or HPLC to assess the 48‐hour time course of risperidone and olanzapine. Urine was assayed for free and glucuronidated drugs. Results When olanzapine was administered with probenecid, statistically significant differences were observed between plasma pharmacokinetic parameters compared with olanzapine administered alone (maximum concentration, P < .05; area under the plasma concentration–time curve from time zero to 24 hours, P < .01). Clearance was not significantly different between the treatment phases. Risperidone pharmacokinetic parameters were not significantly different (all parameters, P > .05). Conclusion Inhibition of uridine diphosphoglucuronate–glucuronosyltransferase appeared to influence the disposition of olanzapine but not risperidone. Phase 2 metabolism may significantly influence the disposition of antipsychotic drugs and may be an important aspect of the variability in metabolism, participation in drug‐drug interactions, and clinical response to some antipsychotic agents. Clinical Pharmacology & Therapeutics (2002) 71 , 30–38; doi: 10.1067/mcp.2002.119815