Developmental changes in the ovine blood brain barrier and pharmacokinetics of valproic acid: A microdialysis study

With its broad spectrum of activities, valproic acid (VPA) has been and will remain an important therapeutic agent in the treatment of various types of epilepsy and other neurological related illnesses, such as bipolar disorder and migraine. The treatment population is not age or gender specific and the potential for fetal and neonatal exposure to VPA is possible. The current understanding of the developmental changes in the blood brain barrier (BBB) to xenobiotics, including VPA, is limited. To assess the relationship between the developmental changes in the BBB and the permeability of the barrier to VPA, a sequential infusion study with 5 escalating doses of VPA was conducted. A paired study with VPA-only infusion and VPA/probenecid co-infusion was also undertaken to assess the mechanism(s) governing VPA transport across the BBB.;From the VPA concentration vs. time profile, VPA crossed the BBB rapidly and reached close to steady state concentration during the first hr of infusion. The rapid entry of VPA into the brain immediately after the initial bolus loading dose suggested that the entry of VPA into the brain was not limited. However, the less than unity in the ratio between ECF/CSF VPA concentrations and the unbound VPA plasma concentration during the steady state period suggested that an active efflux mechanism(s) was limiting the VPA concentration in the ECF and CSF.;Probenecid, a known anion transport inhibitor, was co-infused with VPA in an attempt to inhibit the efflux transport mechanism(s). Results from this paired study did not show any change in the previously observed relationship between ECF or CSF [VPA] and the unbound VPA plasma concentration. However, these results do not exclude the possibility of an increase in intracellular accumulation of VPA in the brain tissue as observed by Scism et al. , 2000.;The elimination of VPA has been reported to be a non-linear process and is best described with Michaelis-Menten kinetics (Ichimura et al. , 1985; Wong et al., 2001). In the 5-step infusion study, results suggested that VPA elimination was a pseudolinear process. In both mid-and late-gestation fetal studies, the plot of the unbound VPA plasma concentration vs. infusion rate was linear for all 5 infusion steps.;The pharmacological effects of probenecid are not limited to the inhibition of transporters, but include the competitive inhibition of the glucuronidation process. In the newborn lamb and non-pregnant ewe, 70% of the administered VPA dose is eliminated by the formation of VPA glucuronide (Kumar et al., 2000a and Wong et al., 2001). In the VPA/probenecid co-infusion study, inhibition of VPA elimination by probenecid was observed during the post-VPA infusion period when the molar concentration ratio of probenecid to VPA increased. (Abstract shortened by UMI.)...