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

doi:10.1007/s11095-021-03003-1

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

Pharmaceutical Sciences

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

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.

Original language	English
Pages (from-to)	113-125
Number of pages	13
Journal	Pharmaceutical Research
Volume	38
Issue number	1
DOIs	https://doi.org/10.1007/s11095-021-03003-1
State	Published - 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.

Keywords

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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10.1007/s11095-021-03003-1

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

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 = "MCT8, P-glycoprotein, blood-brain barrier, monocarboxylate transporter, phenytoin",

author = "Ryuta Jomura and Akanuma, {Shin ichi} and Bj{\"o}rn Bauer and Yukiko Yoshida and Yoshiyuki Kubo and Hosoya, {Ken ichi}",

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: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.",

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AU - Jomura, Ryuta

AU - Akanuma, Shin ichi

AU - Bauer, Björn

AU - Yoshida, Yukiko

AU - Kubo, Yoshiyuki

AU - Hosoya, Ken ichi

N1 - 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.

PY - 2021/1

Y1 - 2021/1

N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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