Ondansetron is primarily eliminated via hepatic metabolism; thus,
liver disease may affect its clearance. The pharmacokinetics of
ondansetron in patients with different degrees of
hepatic insufficiency (N = 12 with hepatic impairment, as categorized by Pugh's classification method) were assessed and the results compared with results for age- and gender-matched control subjects with normal liver function (n = 12). A secondary objective was to correlate the Pugh method of assessing hepatic impairment and quantitative metabolic markers used to assess hepatic function (
antipyrine clearance and
indocyanine green clearance) with changes in the pharmacokinetics of
ondansetron. This was an open-label study in which 8 mg
ondansetron was given orally and intravenously, following a randomized crossover design. Clearance of
ondansetron was lower among patients with hepatic impairment that control subjects. After a single, oral dose of
ondansetron, mean absolute bioavailability increased markedly with increased
hepatic insufficiency (approaching 100% in the group with severe hepatic impairment versus 66% for control subjects). These data suggest that there is a reduced first-pass effect in patients with
liver disease resulting in a higher AUC0-infinity. A correlation existed between clearance of
ondansetron and decreased
antipyrine clearance; a smaller correlation existed between
ondansetron clearance and
indocyanine green clearance. Mean percent of
ondansetron bound to
plasma proteins was significantly lower in patients with
liver disease than in control subjects. None of the patients experienced any severe adverse reactions attributed to
ondansetron. A reduction in the clearance of
ondansetron is associated with increasing degrees of
hepatic insufficiency; therefore, patients with severe hepatic impairment (Pugh score of > 9) should have their daily dose of
ondansetron limited to 8 mg (or 0.15 mg/kg).