Carbamazepine/valproic acid interaction in man and rhesus monkey

Sodium valproate (VPA) was administered for 1 week (1 g b.i.d.) to seven epileptic patients receiving chronic carbamazepine (CBZ) therapy. Steady-state CBZ levels determined before and after VPA therapy were reduced by 3-59% in six patients and were unchanged in one patient. The plasma concentration ratio of carbamazepine-10,11-epoxide ( CBZE ) to CBZ increased in all patients by 11-500%. The plasma binding of CBZ was determined in six healthy volunteers given a single 400 mg CBZ dose with and without the coadministration of 1 g VPA in a cross-over design. The mean CBZ free-fraction was increased in three of the subjects (p = 0.008-0.031), decreased in one subject (p less than 0.002), and remained unchanged in two subjects when VPA was administered. Four male rhesus monkeys were infused intravenously with CBZ (15 mg h-1) for 5 days and then three consecutive 24-h infusions were given: I, CBZ alone; II, CBZ with 75 mg h-1 VPA; III, CBZ with 150 mg h-1 VPA. The mean free-fraction of CBZ and CBZE increased during infusions II and III from 31.5 +/- 2.7% to 33.6 +/- 2.6% (p less than 0.05) and 37.7 +/- 1.3% (p less than 0.01) for CBZ and from 46.9 +/- 9.2% to 53.6 +/- 5.7% (p greater than 0.05) and 60.1 +/- 4.0% (p less than 0.01) for CBZE . The clearance of free CBZ declined from 7.96 +/- 1.75 to 4.84 +/- 1.26 (p less than 0.01) and 4.12 +/- 1.75 (p less than 0.01) 1 kg-1h-1 during infusions II and III, respectively. The mean free CBZE /CBZ ratio increased from 0.12 +/- 0.03 to 0.24 +/- 0.03 and 0.36 +/- 0.04 during infusions II and III, respectively (p less than 0.001). These findings indicate a decrease in the elimination clearance of CBZE possibly coupled with a decrease in its formation clearance.(ABSTRACT TRUNCATED AT 250 WORDS)