Dose-dependent metabolism of carbamazepine in humans.

Abstract

48-h steady-state metabolic balance studies were carried out in 17 adults receiving long-term anticonvulsant monotherapy. With increasing carbamazepine dosage (1) carbamazepine overall plasma apparent clearance (CL/F), (2) plasma clearance of carbamazepine to urinary carbamazepine-10,11-epoxide, (3) plasma clearance of carbamazepine-10,11-epoxide to urinary unconjugated carbamazepine-10,11-trans-diol and (4) plasma clearances of carbamazepine to urinary 2- and 3-hydroxy carbamazepine all increased. However, with increasing carbamazepine dose there was no increase in the clearance of carbamazepine to (5) its acridan derivative in urine or of (6) the diol, phenolic or acridan metabolites to their metabolically subsequent conjugates excreted in urine. These findings are consistent with ongoing dose-dependent autoinduction of carbamazepine metabolism along the first two stages, but not the final stage, of the epoxide-diol pathway and, to a lesser extent, along pathways yielding phenolic metabolites. However, conjugations of the various plasma phase I metabolites of carbamazepine are not dose-dependent. Plasma concentration ratios of substances involved in consecutive stages of the epoxide-diol pathway, as in previous published studies, suggested apparent dose dependence of the epoxide-->unconjugated diol stage only. Presumably, increased flux along the first two stages of the full epoxide-diol pathway reduces plasma carbamazepine and carbamazepine-10,11-epoxide concentrations largely in parallel, concealing the dose dependence of the conversion of carbamazepine to its epoxide.