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

• Published in: Pharmaceutical research Vol. 38; no. 1; pp. 113 - 125
• Main Authors: Jomura, Ryuta, Akanuma, Shin-ichi, Bauer, Björn, Yoshida, Yukiko, Kubo, Yoshiyuki, Hosoya, Ken-ichi
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.01.2021; Springer Nature B.V
• Subjects: Animals; Anticonvulsants - administration & dosage; Anticonvulsants - pharmacokinetics; ATP Binding Cassette Transporter, Subfamily B - genetics; ATP Binding Cassette Transporter, Subfamily B - metabolism; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Blood-brain barrier; Blood-Brain Barrier - metabolism; Brain slice preparation; Capillaries; Female; Gene expression; Glycoproteins; Half-Life; Male; Medical Law; Mice; Mice, Transgenic; Models, Animal; Monocarboxylic Acid Transporters - metabolism; Oocytes; P-Glycoprotein; Perfusion; Pharmacology/Toxicology; Pharmacy; Phenytoin; Phenytoin - administration & dosage; Phenytoin - pharmacokinetics; Rats; Research Paper; Symporters - metabolism; Xenopus; blood-brain barrier; P-glycoprotein; monocarboxylate transporter; phenytoin; MCT8
• ISSN: 0724-8741; 1573-904X; 1573-904X
• DOI: 10.1007/s11095-021-03003-1

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 [ 14 C]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 [ 14 C]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.