DOSE-DEPENDENT METABOLISM OF CARBAMAZEPINE IN HUMANS

48-h steady-state metabolic balance studies were carried out in 17 adu lts receiving long-term anticonvulsant monotherapy. With increasing ca rbamazepine dosage (1) carbamazepine overall plasma apparent clearance (CL/F), (2) plasma clearance of carbamazepine to urinary carbamazepin e-10,11-epoxide, (3) plasma clearance of carbamazepine-10,11-epoxide t o urinary unconjugated carbamazepine-10,11-trans-diol and (4) plasma c learances of carbamazepine to urinary 2- and S-hydroxy carbamazepine a ll increased. However, with increasing carbamazepine dose there was no increase in the clearance of carbamazepine to (5) its acridan derivat ive in urine or of (6) the diol, phenolic or acridan metabolites to th eir metabolically subsequent conjugates excreted in urine. These findi ngs are consistent with ongoing dose-dependent autoinduction of carbam azepine 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 pl asma phase I metabolites of carbamazepine are not dose-dependent. Plas ma concentration ratios of substances involved in consecutive stages o f the epoxide-diol pathway, as in previous published studies, suggeste d apparent dose dependence of the epoxide --> unconjugated diol stage only. Presumably, increased flux along the first two stages of the ful l 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.