Bioavailability of calcium valproate in normal men compared with the free acid and sodium salt

Calcium valproate has been formulated into tablets containing the equivalent of 250 mg valproic acid (VPA). The bioequivalence of this preparation (Valontin, Parke-Davis) has been studied in 12 normal adult males in parallel with other products containing the free acid (Depakene capsules, Abbott) and the sodium salt (Depakene syrup, Abbott). Each subject received a single 500-mg oral dose of each product at 2-week intervals in a randomized three-way crossover study. Assays were carried out for VPA in blood and urine specimens which were collected over extended time periods. Peak plasma levels were attained on the average within 30 min with the syrup, 1.13 h with the capsules, and 1.38 h with the tablets. There were no significant differences in the peak plasma levels attained with the three products, or in the plasma half-lives of VPA and areas under the time-concentration curves. The plasma level curves appeared to be biexponential, with terminal half-lives that averaged 16.6 h. One subject showed a remarkably long half-life (28-38 h) after each of the three doses, indicating the possibility of genetic differences between individuals in the disposition of VPA. The urinary excretion of VPA in most subjects ran parallel to the plasma levels and could not be detected 96 h after dosing; however, the subject with the long plasma half-life continued to excrete VPA in his urine for at least 2 additional days. The mean recovery of VPA in 6-day urine represented 12-14% of the dose and ranged from 5.5 to 27.9% in different individuals. There were no significant differences between the three formulations in the pattern of urinary excretion.