Abstracts

Interpatient variability in absorption, protein binding, and activity of glucuronidating enzymes and beta-oxidation enzymes of valproic acid is poorly described in the elderly population. Our goal was to develop a method to determine the pharmacokinetics and bioavailability of valproic acid (VPA) in younger (ages 18-50) and elderly subjects (ages 65-74 and [gt]75) in patients on maintenance therapy. The initial pharmacokinetic data for the first 12 patients (8 younger adults and 4 elderly) is reported. The non-radioactive, stable isotope form of valproic acid, [13C]4-VPA was synthesized by Isotec and formulated in ampoules in an identical fashion to Depacon[reg] by the University of Iowa Division of Pharmaceutical Services. An intravenous dose (250 mg) of a stable isotope form of valproate, [13C]4-VPA, was given by IV infusion over 15 min replacing 250 mg of the AM oral dose. Serial blood samples were obtained over 96 hr and VPA and [13C]4-VPA were measured in plasma by GC-MS as their tert-butyl dimethylsilyl derivatives. Plasma protein binding was determined by membrane ultrafiltration. Non-compartmental PK analysis was performed with WinNonlin 4.1. The average age of the younger group was 38 (n=8) compared to the mean age of 70 for the older group (n =4). The stable isotope was well tolerated in all patients. Valproic acid was completely bioavailable after oral dosing for both groups (F not significantly different from 1.0). Half lives were 12.6 [plusmn]2.3 h in the younger group vs. 10.9 [plusmn] 2.4 h in the elderly group (N.S.). The clearance values were not significantly different (741 [plusmn] 210 mL/hr [ndash] young vs. 904 [plusmn] 288 mL/hr [ndash]old). Free fraction was 0.13 [plusmn] 0.03 in young vs. 0.11 [plusmn] 0.01 in old. The mean volume of distribution was also not significantly different (13.5 [plusmn] 5.0 L in young vs. 13.5 [plusmn] 2.2 L in elderly). In this preliminary report, we have demonstrated the utility of a stable isotope technique for the determination of valproic acid pharmacokinetics in patients on maintenance therapy. Due to the small numbers of elderly patients recruited so far, no significant effect of aging was observed. A total of 20 younger subjects and 40 elderly subjects (in 2 age groups) will be recruited to complete the study. The half-lives, volume, and clearance values are similar to those reported after single doses of intravenous VPA. (Supported by NIH-NINDS P50-NS16308 and M01-RR00400 and Abbott Laboratories.)