Carbamazepine protein binding and disposition in pregnancy

The pregnancies of five women with epilepsy treated with carbamazepine monotherapy were studied prospectively. Free and total serum concentrations of carbamazepine and its epoxide and dihydrodiol metabolites were analyzed at monthly intervals from the first trimester through 8 weeks postpartum. Assays were by high performance liquid chromatography, and free compounds were separated by ultrafiltration. The mean intrinsic clearance of carbamazepine (clearance of free drug corrected for changes in maternal body weight) did not change appreciably during pregnancy and the postpartum period. The mean free fractions of carbamazepine and the epoxide were elevated during pregnancy (0.25 and 0.50) compared with postpartum (0.22 and 0.43). Mean total maternal carbamazepine and epoxide concentrations were 40 and 48% higher than neonatal levels at birth, but maternal and neonatal free concentrations agreed closely. The ratio of epoxide to parent drug increased during pregnancy, as reported by other authors. Evidence is presented that this may be a result of inhibition of further biotransformation of the epoxide rather than of increased production. Two patients missed at least one dose of carbamazepine during labor, resulting in markedly reduced serum concentrations at delivery.