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 |
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Pages (from-to) | 113-125 |
Number of pages | 13 |
Journal | Pharmaceutical Research |
Volume | 38 |
Issue number | 1 |
DOIs | |
State | Published - Jan 2021 |
Bibliographical note
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)