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

Ryuta Jomura, Shin ichi Akanuma, Björn Bauer, Yukiko Yoshida, Yoshiyuki Kubo, Ken ichi Hosoya

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


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.

Original languageEnglish
Pages (from-to)113-125
Number of pages13
JournalPharmaceutical Research
Issue number1
StatePublished - Jan 2021

Bibliographical note

Funding Information:
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.

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.


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

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)


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