Blood–Brain Barrier Transport of Valproic Acid

Abstract

Valproic acid distribution in brain is less than that of other anticonvulsants such as phenytoin or phenobarbital. Possible mechanisms for this decreased distribution space in brain include (a) increased plasma protein binding of valproate relative to the other anticonvulsants and (b) asymmetric blood-brain barrier (BBB) transport of valproate such that the brain-to-blood flux exceeds the blood-to-brain flux. These mechanisms are investigated in the present studies using the intracarotid injection technique in rats and rabbits. In the rat, the brain uptake index (BUI) of [14C]valproate relative to [3H]water is 51 +/- 6%, indicating the blood-to-brain transport of water is twofold greater than that of valproate. However, the BUI of [14C]valproate relative to [3H]water decreased with time after carotid injection during a 4-min washout period, which indicates that brain-to-blood transport of valproate is greater than that of water. This suggests that the permeability of the BBB to valproate is polarized, with antiluminal permeability being much greater than luminal permeability. In rabbits, the BUI of [14C]valproate is 47 +/- 7% in newborns and 17 +/- 6% in adult animals. However, the high drug extraction in newborns may be attributed to decreased cerebral blood flow in the neonate as the BBB permeability-surface area (PS) products are unchanged (e.g., PS = 0.13 and 0.11 ml min-1 X g-1 in the newborn and adult rabbit, respectively). With regard to plasma protein binding effects on valproate transport, brain valproate uptake was also measured in the presence of human, lamb, pig, rat, horse, goat, hamster, dog, and mouse sera. Higher brain uptakes were observed when the unbound fraction of drug increased. However, our data indicate that a fraction of the valproic acid entering the capillaries bound to plasma proteins had the capacity to equilibrate with brain because of enhanced drug dissociation from albumin in the brain microcirculation. Since plasma protein-bound valproate is available for uptake by brain, the major factor underlying the diminished distribution of the drug in brain appears to be the asymmetric transport properties of the BBB to valproic acid.

Valproic Acid Is Not a Substrate for P-glycoprotein or Multidrug Resistance Proteins 1 and 2 in a Number of in Vitro and in Vivo Transport Assays

“…The lack of probenecid to increase the penetration of VPA into either extracellular fluid or brain tissue of rats is in contrast to several previous reports in which probenecid was shown to elevate brain, CSF, or brain dialysate levels. However, after our initial study in dogs (Frey and Löscher, 1978), most subsequent studies on probenecid's effects on VPA brain distribution were done in rabbits (e.g., Cornford et al, 1985;Adkison et al, 1994Adkison et al, , 1996Scism et al, 2000), so that interspecies differences could be involved in the apparent discrepancies between the present and previous studies. This possibility is also suggested by a study of Golden et al (1993), in which probenecid was shown to decrease VPA concentrations in the CSF of rats, whereas we found an increase in CSF concentrations of VPA following probenecid in dogs (Frey and Löscher, 1978).…”

Molecular Cloning and Characterization of a New Multispecific Organic Anion Transporter from Rat Brain

“…estrone sulfate and ochratoxin A); however, the substrate selectivity of these two families overlaps little. The transporter(s) responsible for the efflux transport, via BBB and/or BCSFB, of naphthol glucuronide, dideoxyinosine, azidodeoxythymidine, and valproic acid has not been identified (27)(28)(29)(30). The functional analysis and localization of oatp1, oatp2, and OAT3 will clarify the molecular mechanisms of the organic anion transport in the brain.…”

Small molecular drug transfer across the blood-brain barrier via carrier-mediated transport systems

“…29 There are several studies showing that an anticonvulsant, valproic acid, is efficiently transported across the BBB. 30,31 When uptake of valproic acid was measured by an in situ brain perfusion method, it was saturable, with Km values between 10 and 20 mM, depending on the measured brain regions. Uptake of valproic acid was reduced in the presence of medium-chain fatty acids such as hexanoate, octanoate, and decanoate, but not propionate or butyrate, indicating that valproic acid is taken up into the brain via a transport system for medium-chain fatty acids, not short-chain fatty acids.…”