Effect of phenytoin, carbamazepine, and valproic acid on caffeine metabolism.

Three groups of non-smoking epileptic patients without liver disease receiving antiepileptic monotherapy have been compared with 10 healthy non-smoking volunteers. Group 1 received phenytoin (n = 10), Group 2 carbamazepine (n = 10) and Group 3 valproic acid (n = 6). Cytochrome P-450 activity was monitored by measuring urinary 6-beta-hydroxycortisol output and systemic antipyrine clearance. Both, 6-beta-hydroxycortisol output and antipyrine clearance were significantly enhanced in patients on phenytoin and carbamazepine, but not in those on valproic acid. On the other hand, phenytoin alone increased the clearance of caffeine from 1.5 (controls) to 3.6 ml.min-1.kg-1, and reduced its half life from 4.8 to 2.4 h. Carbamazepine and valproic acid had no effect on caffeine metabolism. The results are in keeping with the well known heterogeneity of the hepatic monooxygenase system, as phenytoin and carbamazepine induce different panels of cytochrome P-450 isoenzymes. Phenytoin treatment may impair the validity of the caffeine liver function test.