Effects of pregnancy on various pathways of human antiepileptic drug metabolism.

Ratios of phenytoin and carbamazepine doses to steady-state plasma concentrations of the drugs (apparent clearances) increase in pregnant women. Mean phenytoin clearance to urinary unconjugated p-hydroxyphenytoin increased from 0.28 +/- SD 0.18 to 0.74 +/- SD 0.37 L/day in 13 pregnant women; mean clearance to p-hydroxyphenytoin glucuronide increased proportionately less (15.25 +/- SD 5.43 to 31.94 +/- SD 16.30 L/day), the proportion of the metabolite that was conjugated falling from 98.4 +/- SD 0.72% to 97.65 +/- SD 0.67%. Mean clearances to urinary phenytoin and phenytoin-dihydrodiol did not increase. In 10 epileptic women, mean clearances of carbamazepine to urinary (a) carbamazepine-10,11-epoxide (1.66 +/- SD 1.2 to 3.70 +/- SD 2.09 L/day), (b) unconjugated carbamazepine-10,11-trans-diol (33.93 +/- SD 10.21 to 47.01 +/- SD 19.58 L/day). (c) unconjugated carbamazepine-acridan (0.24 +/- SD 0.12 to 0.47 +/- SD 0.34 L/day), and (d) unconjugated 2-hydroxy-carbamazepine (0.08 +/- SD 0.09 to 0.66 +/- SD 1.14 L/day) all increased during pregnancy. Mean clearance to unconjugated 3-hydroxy-carbamazepine decreased (0.53 +/- SD 0.25 to 0.18 +/- SD 0.23 L/day). In contrast, mean clearances of carbamazepine to the glucuronides of its first stage metabolites (carbamazepine-diol, 2- and 3-hydroxy-carbamazepine and carbamazepine-acridan, respectively) did not increase in pregnancy. The conversion of carbamazepine to carbamazepine-epoxide increased proportionately more than the conversion of carbamazepine-epoxide to carbamazepine-diol. Pregnancy was thus associated with increased microsomal oxidations of phenytoin and carbamazepine, without proportionate increases in the subsequent hydrolysis of carbamazepine-10,11-epoxide and in the O-glucuronidations of the earlier stage metabolites.