Effect of para-aminohippurate on the efflux of valproic acid from the central nervous system of the rabbit.

Recently we investigated the mechanisms mediating the transport of valproic acid (VPA) between blood and brain. In one study efflux of valproic acid (VPA) from rabbit brain was inhibited by probenecid. Efflux of VPA decreased when probenecid was given intravenously but not when probenecid was given by ventriculocisternal (VC) perfusion indicating that the major site of probenecid-sensitive transport was at the brain capillary endothelium and not at the choroid plexus. In another study VPA transport into rat brain was inhibited by para-aminohippurate (PAH). The purpose of the present study were to determine (a) if the efflux of VPA from rabbit brain was also inhibited by PAH, and (b) whether efflux of VPA could occur at the choroid plexus via an PAH-selective transport system. Six control rabbits received VPA by intravenous infusion and tracer concentrations of [3H]VPA and [14C]PAH by VC perfusion. Rabbits in the PAH group (n = 6) received identical treatment with VPA, tracer concentrations of [3H]VPA and [14C]PAH and, in addition, received 20 mM PAH by VC perfusion. PAH had no effect on the VC extraction ratio of [3H]VPA or the steady-state brain concentration of intravenously administered VPA. It is concluded that the efflux of VPA at the rabbit blood-brain barrier is mediated by a transporter different from the PAH-like transporter responsible for the uptake of VPA into rat brain. In addition, the finding that VC perfusion with PAH had no effect on the VC extraction of [3H]VPA provides further evidence that the choroid plexus plays a negligible role in removal of VPA from the CNS.

Uptake of valproic acid into rat brain is mediated by a medium-chain fatty acid transporter.

The uptake of valproic acid (VPA) from blood into several brain regions was investigated using the "in situ" brain perfusion technique in the rat. The uptake kinetics of VPA exhibited partial saturability and trans-stimulation, which indicate the simultaneous presence of carrier-mediated transport and diffusion. The apparent Michaelis constant for the saturable process ranged from 10mM in the cortical regions to 23.5 mM in the thalamus. The uptake of radiotracer VPA was not inhibited by coperfusion of short-chain (

Distribution of unsaturated metabolites of valproate in human and rat brain--pharmacologic relevance?

The concentrations of valproate (VPA) and six of its pharmacologically active, unsaturated metabolites (E-delta 2-VPA, Z-delta 3-VPA, E-delta 3-VPA, E,E-delta 2,3'-VPA, delta 4-VPA, and E-delta 2,4-VPA) were measured in serum and cortical brain samples from 24 patients undergoing epilepsy surgery. Collectively, the six metabolites were present at concentrations < 13% of VPA brain concentrations. Because the six unsaturated metabolites were present at such low brain concentrations, we concluded that these metabolites probably did not contribute significantly to the anticonvulsant effect of VPA. Results from a parallel pharmacodynamic study in rats in which VPA was administered three times daily for 8 weeks supported this conclusion. Only three unsaturated metabolites (E-delta 2-VPA, delta 3-VPA, E,E-delta 2,3'-VPA) were detected in rat brain. No correlation was observed between the time course of anticonvulsant effect [as measured by the timed intravenous pentylenetetrazol (PTZ) test] and the time course of VPA or metabolite concentrations in rat brain. Despite the structural similarity of VPA and its metabolites, striking differences were observed in their serum protein binding and blood-brain distribution properties. In the human brain, VPA and delta 4-VPA exhibited brain-to-free serum concentration ratios that were less than unity. In contrast, compounds with the double bond at the 2- or 3-position had brain:free concentration ratios that were much higher than unity. The structure-distribution relationship observed with VPA and its unsaturated metabolites suggested that these branched-chain fatty acids differ in their asymmetric transport across the blood-brain barrier (BBB).

Role of choroid plexus epithelium in the removal of valproic acid from the central nervous system.

Previous experiments suggest the primary route of valproic acid (VPA) removal from the rabbit central nervous system (CNS) is by probenecid-sensitive transporters at the blood-brain barrier but not at the choroid plexus. The purpose of this study was to determine if other transport mechanisms at the choroid plexus played a significant role in the removal of VPA from the CNS. In six rabbits, silicone oil was perfused into both cerebral ventricles and out through the cisterna magna to physically block exchange of VPA between cerebrospinal fluid (CSF) and blood and between brain and CSF. In six control rabbits, perfusion was performed with mock CSF. Both groups received a loading dose followed by continuous intravenous infusion of VPA for 210 min. Ventriculocisternal perfusion with silicone oil had no significant effect on the steady-state brain concentrations or brain-to-plasma concentration ratios of VPA, further confirming that efflux of VPA at the choroid plexus is negligible.

Contribution of probenecid-sensitive anion transport processes at the brain capillary endothelium and choroid plexus to the efficient efflux of valproic acid from the central nervous system.

The steady-state brain-to-free plasma concentration ratio of valproic acid (VPA) is well below unity, which suggests that it is efficiently removed from the central nervous system (CNS) by specialized transport processes. The purpose of this study was to determine whether probenecid (PBD)-sensitive anion transporters at the choroidal epithelium and brain capillary endothelium are involved in the clearance of VPA from the CNS of the rabbit. Unlabeled VPA was infused i.v. to achieve a steady-state plasma concentration while a tracer concentration of 3H-VPA was introduced into the ventricles by ventriculocisternal (VC) perfusion. In two treatment groups, PBD was administered by direct placement into the VC perfusate or by a combination of an i.v. priming dose and continuous infusion. In the control group, no other treatments were given. PBD administered by either route had no effect on the steady-state VC extraction of 3H-VPA (approximately 57%). Coadministration of PBD through the VC perfusate had no apparent effect on the blood-brain distribution of unlabeled VPA. In the i.v. PBD group, the concentration in the brain of systemically administered VPA increased 1.5- to 2-fold in all regions compared with that in control animals. Because neither the total nor the free plasma concentration of VPA was affected by PBD, the increase in brain VPA concentration reflected a blockade of VPA efflux across the brain capillary endothelium. These results suggest that PBD-sensitive transport at the brain capillary endothelium is the main route of VPA efflux from the CNS.