DISPOSITION AND PROTEIN-BINDING OF VALPROIC ACID IN THE DEVELOPING RAT

The disposition of valproic acid (VPA) in serum and brain tissue was e xamined in developing rats (5, 10, 20, and 60 days postpartum) followi ng 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 VP A administration, as well as after in vitro addition of VPA (8-2400 mu g/ml) to pooled rat serum from naive animals of each age. Concentrati on-time data for VPA in serum and brain tissue were fit simultaneously , assuming first-order absorption from the peritoneal injection site a nd first order transfer of drug between serum and brain tissue. Kineti c 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 recircul ation, a well-described facet of VPA disposition in adult rats, was no t evident from examination of the serum concentration-time profile in animals prior to the time of weaning. A progressive increase in the bi nding of VPA to proteins in serum was observed during postnatal develo pment. The bound fraction determined ex vivo was less than that determ ined in vitro for all age groups, suggesting the possibility of compet ition for VPA binding sites by metabolite(s) formed in vivo.