Induction of hepatic and presystemic metabolism of antipyrine in the mice: rifampicin versus rifabutin.

The effects of hepatic and presystemic enzyme induction on the bioavailability (F) and disposition of antipyrine after repeated rifampicin (RFM) and rifabutin (RBT) exposure were studied in mice. ICR mice were divided to receive 4 daily oral dosing of either the dosing vehicle or 50 mg/kg of REM or RBT. At the completion of rifamycin dosing, the pharmacokinetics of antipyrine were assessed following either a single 50 mg/kg oral dose or a 20 mg/kg intravenous dose. Blood samples were collected (n=4/timepoint) over a 6 h period. The content of P450 in the liver and small intestine (GI) was also assessed in parallel. Systemic antipyrine clearance (CL) increased from 31.8 ml/min/kg (controls) by 64% and 42% following repeated exposure to RFM and RBT, respectively. Estimate of F for antipyrine decreased from 0.97 in controls to 0.58 and 0.82 in animals treated with RFM and RBT, respectively. The content of P450 (nmol/mg protein) in the liver increased from 0.61 (control) to 1.36 following RFM and 0.82 for RBT, while no significant changes were observed for the GI tract. The i.v. dosing data confirmed the induction of antipyrine metabolism in the liver by both rifamycins yet the induction potential was approximately 1/3 lower for RBT. This difference was consistent with the changes observed in the hepatic P450 protein content, but this alone could not account for the reduction in the F for antipyrine. Therefore, predictions for changes in F of an interacting agent should not be judged solely on the basis of the metabolic status of the liver. The relative contribution of metabolic induction and presystemic drug loss to bioavailability/absorption should also be further delineated for its relevance to poly-pharmacy in patients likely to receive long-term rifamycin based treatment.