Participation of Monocarboxylate Transporter 8, But Not P-Glycoprotein, in Carrier-Mediated Cerebral Elimination of Phenytoin across the Blood-Brain Barrier



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.


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.


[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.


Our data suggest that MCT8 at the BBB participates in phenytoin efflux transport from the brain to the blood.

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ATP-binding cassette


Blood-brain barrier


Brain efflux index


Breast cancer resistance protein




Cerebral extracellular fluid


Complementary DNA


Complementary RNA


Cytochrome P450




4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid


Monocarboxylate transporter


Multidrug resistance-associated protein

n :

Group sizes




Standard deviation


Single nucleotide polymorphism

X :



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The authors thank Mr. Kosuke Tajima (University of Toyama) for helping with the mRNA expression analysis for MCTs. This research was supported by The Mochida Memorial Foundation for Medical and Pharmaceutical Research, The Research Foundation for Pharmaceutical Sciences, and Japan Society for the Promotion of Science (JSPS) KAKENHI [Grant Numbers JP16K08365 (to S.A.), JP16H05110 (to K.H.), and JP19K07160 (to S.A.)]. This project was also supported by Grant 1R01NS079507 from the U.S. National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (to B.B.). The content is solely the responsibility of the authors, and it does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke or the NIH. All authors declare no conflict of interest.

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R.J., S.A., B.B., and Y.Y. performed the experiments; R.J., S.A., B.B., Y.K., and H.K. designed the experiments and analyzed the data.; and R.J. and S.A. wrote the manuscript. All authors read the final version of the manuscript.

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Correspondence to Shin-ichi Akanuma.

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Jomura, R., Akanuma, Si., Bauer, B. et al. Participation of Monocarboxylate Transporter 8, But Not P-Glycoprotein, in Carrier-Mediated Cerebral Elimination of Phenytoin across the Blood-Brain Barrier. Pharm Res 38, 113–125 (2021).

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Key words

  • blood-brain barrier
  • MCT8
  • monocarboxylate transporter
  • phenytoin
  • P-glycoprotein