CARBAMAZEPINE METABOLISM IN MAN INDUCTION AND PHARMACOGENETIC ASPECTS

The metabolism of carbamazepine (CBZ) was studied in 3 groups of subjects: 6 healthy volunteers given a single dose of 200 mg carbamazepine; 4 epileptic patients on carbamazepine monotherapy; and 5 patients receiving carbamazepine in combination with other anticonvulsants. Carbamazepine kinetics in the patients were investigated by use of 15N-CBZ. The mean plasma clearance of carbamazepine were 19.8, 54.6 and 113.3 ml/h per kg in groups 1, 2, and 3, respectively. The increased clearance in the patients was mainly due to an induction of the epoxide-diol pathway, as reflected by an increased urinary excretion of the trans-CBZ-diol metabolite. The urinary excretion (as a percentage of the administered dose) of 9-hydroxymethyl-10-carboamoylacridan (9-OH-CBZ) was also increased, whereas the excretion of 2-OH-CBZ and 3-OH-CBZ [2-hydroxycarbamazepine and 3-hydroxycarbamazepine] in groups 2 and 3 were decreased in comparison with group 1. 9-OH-CBZ is formed from carbamazepine-10,11-epoxide (CBZ-E) or trans-CBZ-diol, the formation of 9-OH-CBZ was investigated in 3 patients with trigeminal neuralgia treated with carbamazepine or CBZ-E as monotherapy on separate occasions. The urinary excretion of 9-OH-CBZ was 1.9, 3.3 and 4.0% of the trans-CBZ-diol excretion during CBZ-E therapy and 23, 32 and 24%, respectively, during carbamazepine therapy is formed via the epoxide-diol pathway. Data on plasma concentrations of carbamazepine and CBZ-E, and on urinary excretion of trans-CBZ-diol from 4 patients on carbamazepine therapy were used to calculate the plasma clearance of CBZ-E. The hydration of CBZ-E during carbamazepine therapy was found to be induced, but to a lesser extent than the expoxidation and oxidative metabolic reactions of some other drugs was also studied in 8 healthy volunteers. Carbamazepine epoxidation was not correlated to 4-hydroxylation debrisoquine, oxidation of sparteine, 3- and 4-hydroxylation demethylation of antipyrine, demethylation of amitriptyline, or total metabolism of theophylline.