Participation of Monocarboxylate Transporter 8, But Not P-Glycoprotein, in Carrier-Mediated Cerebral Elimination of Phenytoin across the Blood-Brain Barrier
- 1 January 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Pharmaceutical Research
- Vol. 38 (1), 113-125
- https://doi.org/10.1007/s11095-021-03003-1
Abstract
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 [14C]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 [14C]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.Keywords
Funding Information
- Japan Society for the Promotion of Science (JP16K08365, JP19K07160)
- JAPAN SCIETY FOR THE PROMOTION OF SCIENCE (JP16H05110)
- The Mochida Memorial Foundation for Medical and Pharmaceutical Research (n/a)
- The Research Foundation for Pharmaceutical Sciences (n/a)
- the U.S. National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (1R01NS079507)
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