Journal
PHARMACEUTICAL RESEARCH
Volume 38, Issue 1, Pages 113-125Publisher
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11095-021-03003-1
Keywords
blood-brain barrier; MCT8; monocarboxylate transporter; phenytoin; P-glycoprotein
Funding
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Research Foundation for Pharmaceutical Sciences
- Japan Society for the Promotion of Science (JSPS) KAKENHI [JP16K08365, JP16H05110, JP19K07160]
- U.S. National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke [1R01NS079507]
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The study investigated the transport of phenytoin across the blood-brain barrier (BBB), identifying that MCT8 participates in the efflux of phenytoin from the brain to the blood. Meanwhile, P-gp did not affect the efflux of phenytoin from the brain.
Purpose In this study, we investigated in detail the transport of phenytoin across the blood-brain barrier (BBB) to identify the transporter(s) involved in BBB-mediated phenytoin efflux from the brain. Methods We evaluated the brain-to-blood efflux transport of phenytoin in vivo by determining the brain efflux index (BEI) and uptake in brain slices. We additionally conducted brain perfusion experiments and BEI studies in P-glycoprotein (P-gp)-deficient mice. In addition, we determined the mRNA expression of monocarboxylate transporter (MCT) in isolated brain capillaries and performed phenytoin uptake studies in MCT-expressing Xenopus oocytes. Results [C-14]Phenytoin brain efflux was time-dependent with a half-life of 17 min in rats and 31 min in mice. Intracerebral pre-administration of unlabeled phenytoin attenuated BBB-mediated phenytoin efflux transport, suggesting carrier-mediated phenytoin efflux transport across the BBB. Pre-administration of P-gp substrates in rats and genetic P-gp deficiency in mice did not affect BBB-mediated phenytoin efflux transport. In contrast, pre-administration of MCT8 inhibitors attenuated phenytoin efflux. Moreover, rat MCT8-expressing Xenopus oocytes exhibited [C-14]phenytoin uptake, which was inhibited by unlabeled phenytoin. Conclusion Our data suggest that MCT8 at the BBB participates in phenytoin efflux transport from the brain to the blood.
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