Disposition and protein binding of valproic acid in the developing rat

The disposition of valproic acid (VPA) in serum and brain tissue was examined in developing rats (5, 10, 20, and 60 days postpartum) following both single and multiple intraperitoneal doses of VPA. The binding of VPA to proteins in serum was determined ex vivo by ultrafiltration for each age group in pooled serum at various time points following VPA administration, as well as after in vitro addition of VPA (8-2400 μg/ml) to pooled rat serum from naive animals of each age. Concentration-time data for VPA in serum and brain tissue were fit simultaneously, assuming first-order absorption from the peritoneal injection site and first-order transfer of drug between serum and brain tissue. Kinetic analysis revealed that total clearance increased with postnatal age, whereas the volume of distribution and brain-to-serum partitioning of VPA decreased during development. Furthermore, enterohepatic recirculation, a well-described facet of VPA disposition in adult rats, was not evident from examination of the serum concentration-time profile in animals prior to the time of weaning. A progressive increase in the binding of VPA to proteins in serum was observed during postnatal development. The bound fraction determined ex vivo was less than that determined in vitro for all age groups, suggesting the possibility of competition for VPA binding sites by metabolite(s) formed in vivo.