Influence of the enzyme induction by rifampicin on its presystemic metabolism

Abstract Rifampicin clearance increases during multiple dose therapy due to its known induction of hepatic enzymes, which leads to autoinduction of its own metabolism. Therefore, we investigated the pharmacokinetics of rifampicin (RMP) and its major metabolites, 25-desacetyl- (D-RMP) and 3-formyl-RMP (F-RMP), in two groups of six patients with active pulmonary tuberculosis who received either chronic oral or intravenous RMP therapy in combination with isoniazid and ethambutol. Serum concentrations of RMP were determined by HPLC at the beginning and after one and three weeks of chronic dosing. It was found that while the volume of distribution of RMP remained constant over the study period, the systematic clearance of RMP increased during multiple dosing. The bioavailability of oral RMP decreased from 93% after a single oral dose to 68% after three weeks. The decrease could not be attributed solely to an increase in hepatic clearance. This suggests that gut wall metabolism may also be induced during chronic therapy with RMP, leading to presystemic clearance of RMP. The metabolites were also eliminated more rapidly after repeated RMP administration (induction of phase II transformations).