The kinetics of carbamazepine using 15N-carbamazepine were investigated in epileptic patients during combined anticonvulsant therapy. The 15N-carbamazepine plasma half-lives ranged from 5.0 to 13.6 hr with a mean of 8.2 hr. These half-lives are appreciably shorter than reported during chronic carbamazepine monotherapy. Predicted steady-state plasma levels and observed plasma levels of carbamazepine were in excellent agreement. Between 32% and 61% of the dose administered is excreted in the urine as carbamazepine-trans-diol, 5.2% to 8.8% as 9-hydroxymethyl-10-carbamoyl acridane, 1% to 1.4% as 10,-11-carbamazepine epoxide, and 0.5% as carbamazepine. The data indicate that it is the epoxide-diol pathway which is induced during long-term treatment. Concomitant therapy with primidone, phenytoin, phenobarbital, ethosuximide, or methsuximide further induces carbamazepine metabolism.

The kinetics of carbamazepine using stable labelled 15N-carbamazepine was studied in 4 epileptic patients who had been treated with it for at least 6 months. There was a decrease in half-life (12.3 +/- 0.8 h) and an increase in total plasma clearance (58.0 +/- 6.5 ml/min) as compared to single dose studies, which provide further evidence that carbamazepine induces its own metabolism during long-term treatment. Analysis of the urinary metabolites indicated induction of the epoxide-trans-diol pathway. Predicted and observed steady-state plasma levels were in good agreement, thus demonstrating that the use of stable labelled drugs is a useful technique to elucidate changes in kinetics and metabolism which may occur in patients during long-term treatment.

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The serum valproic acid levels of 18 maternity patients at the time of delivery were compared with the valproic acid levels in the umbilical cord serum. The levels in the umbilical cord serum were 1.1-4.6 times higher than those in the maternal serum, with a mean value of 1.38. One explanation for this difference apparently is an increased protein binding of valproic acid in the infant's serum. Protein binding was determined in nine patients, in six by equilibrium dialysis and in three by ultrafiltration. The median value of the free fraction of valproic acid was 9.1% (range, 5.8-16.4%) in the umbilical cord serum (equilibrium dialysis) and 15% (range, 12.7-35.3%) in the maternal serum. The difference between the infant and the maternal serum is significant.