Effect of Phenobarbital on Carbamazepine and Its Major Metabolites in Serum, Different Brain Areas, and Urine After Acute and Chronic Administration to Rats

Abstract

The influence of coadministration of phenobarbital (PB) on disposition of carbamazepine (CBZ) and carbamazepine-10,11-epoxide (CBZ-E) in serum and in discrete areas of rat brain, together with its effects on urinary excretion of CBZ, CBZ-E, and trans-10,11-dihydro-10,11-dihydroxycarbamazepine (CBZ-DIOL) were investigated after both acute and chronic administration. Acute coadministration of PB resulted in increased serum CBZ levels, whereas serum CBZ-E levels were initially lower and then higher. In daily urinary excretion, a reduction in both CBZ-E/CBZ ratio and CBZ-DIOL/CBZ ratio was observed. Chronic (30 day) coadministration of PB led to a decrease in serum CBZ levels after the first hour, whereas serum CBZ-E levels were initially higher and then lower. In daily urinary excretion, a decrease in CBZ-E/CBZ ratio and an increase in CBZ-DIOL/CBZ ratio were noted. These results are consistent with an inhibitory interaction and a metabolic induction on both CBZ epoxidation and CBZ-E metabolism in acute and chronic administration, respectively. However, effects on CBZ epoxidation were preferential. In the various brain areas, the effects observed were similar to those noted in serum. In addition, a relevant increase in brain/serum CBZ ratios was observed with chronic coadministration of PB.