Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Pharm Res
2021 Jan 01;381:113-125. doi: 10.1007/s11095-021-03003-1.
Show Gene links
Show Anatomy links
Participation of Monocarboxylate Transporter 8, But Not P-Glycoprotein, in Carrier-Mediated Cerebral Elimination of Phenytoin across the Blood-Brain Barrier.
Jomura R
,
Akanuma SI
,
Bauer B
,
Yoshida Y
,
Kubo Y
,
Hosoya KI
.
???displayArticle.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.
???displayArticle.pubmedLink???
33527223
???displayArticle.pmcLink???PMC8906351 ???displayArticle.link???Pharm Res ???displayArticle.grants???[+]
n/a The Mochida Memorial Foundation for Medical and Pharmaceutical Research, JP19K07160 Japan Society for the Promotion of Science , n/a The Research Foundation for Pharmaceutical Sciences, 1R01NS079507 the U.S. National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke, JP16K08365 Japan Society for the Promotion of Science , R01 NS079507 NINDS NIH HHS , JP16H05110 Japan Sciety for the Promotion of Science
Akanuma,
ATP-binding cassette transporter A1 (ABCA1) deficiency does not attenuate the brain-to-blood efflux transport of human amyloid-beta peptide (1-40) at the blood-brain barrier.
2008, Pubmed
Akanuma,
ATP-binding cassette transporter A1 (ABCA1) deficiency does not attenuate the brain-to-blood efflux transport of human amyloid-beta peptide (1-40) at the blood-brain barrier.
2008,
Pubmed
Akanuma,
Transporter-mediated prostaglandin E₂ elimination across the rat blood-brain barrier and its attenuation by the activation of N-methyl-D-aspartate receptors.
2014,
Pubmed
Akanuma,
Role of l-Type Amino Acid Transporter 1 at the Inner Blood-Retinal Barrier in the Blood-to-Retina Transport of Gabapentin.
2018,
Pubmed
Akanuma,
Organic anion-transporting polypeptide 1a4-mediated heterogeneous distribution of sulforhodamine-101 in rat hepatic lobules.
2019,
Pubmed
,
Xenbase
Bajpai,
Roles of cytochrome P4502C9 and cytochrome P4502C19 in the stereoselective metabolism of phenytoin to its major metabolite.
1996,
Pubmed
Bankstahl,
Knockout of P-glycoprotein does not alter antiepileptic drug efficacy in the intrahippocampal kainate model of mesial temporal lobe epilepsy in mice.
2016,
Pubmed
CARTER,
Use of parenteral diphenylhydantoin (dilantin) sodium in control of status epilepticus.
1958,
Pubmed
Cornford,
Increased blood--brain barrier transport of protein-bound anticonvulsant drugs in the newborn.
1983,
Pubmed
Cui,
Vectorial transport by double-transfected cells expressing the human uptake transporter SLC21A8 and the apical export pump ABCC2.
2001,
Pubmed
El-Sheikh,
Renal glucuronidation and multidrug resistance protein 2-/ multidrug resistance protein 4-mediated efflux of mycophenolic acid: interaction with cyclosporine and tacrolimus.
2014,
Pubmed
Felmlee,
Monocarboxylate Transporters (SLC16): Function, Regulation, and Role in Health and Disease.
2020,
Pubmed
Fisel,
Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy.
2018,
Pubmed
Fohner,
Assessing the clinical impact of CYP2C9 pharmacogenetic variation on phenytoin prescribing practice and patient response in an integrated health system.
2019,
Pubmed
Friesema,
Identification of monocarboxylate transporter 8 as a specific thyroid hormone transporter.
2003,
Pubmed
,
Xenbase
Grube,
Neurosteroid Transport in the Brain: Role of ABC and SLC Transporters.
2018,
Pubmed
Kakee,
Brain efflux index as a novel method of analyzing efflux transport at the blood-brain barrier.
1996,
Pubmed
Kusuhara,
P-Glycoprotein mediates the efflux of quinidine across the blood-brain barrier.
1997,
Pubmed
Kwan,
Early identification of refractory epilepsy.
2000,
Pubmed
Matsson,
Identification of novel specific and general inhibitors of the three major human ATP-binding cassette transporters P-gp, BCRP and MRP2 among registered drugs.
2009,
Pubmed
Mayerl,
Transporters MCT8 and OATP1C1 maintain murine brain thyroid hormone homeostasis.
2014,
Pubmed
Miyake,
Hypothyroidism induced by phenytoin and gabapentin: A Case Report.
2018,
Pubmed
Murakami,
Functional characterization of human monocarboxylate transporter 6 (SLC16A5).
2005,
Pubmed
,
Xenbase
Muzzio,
Tissue distribution and thyroid hormone effects on mRNA abundance for membrane transporters Mct8, Mct10, and organic anion-transporting polypeptides (Oatps) in a teleost fish.
2014,
Pubmed
Müller,
Expression pattern of thyroid hormone transporters in the postnatal mouse brain.
2014,
Pubmed
Ohtsuki,
Contribution of carrier-mediated transport systems to the blood-brain barrier as a supporting and protecting interface for the brain; importance for CNS drug discovery and development.
2007,
Pubmed
Okura,
Involvement of the pyrilamine transporter, a putative organic cation transporter, in blood-brain barrier transport of oxycodone.
2008,
Pubmed
Potschka,
In vivo evidence for P-glycoprotein-mediated transport of phenytoin at the blood-brain barrier of rats.
2001,
Pubmed
Ramasamy,
Influence of CYP2C9 genetic polymorphism and undernourishment on plasma-free phenytoin concentrations in epileptic patients.
2010,
Pubmed
Roberts,
Expression of the thyroid hormone transporters monocarboxylate transporter-8 (SLC16A2) and organic ion transporter-14 (SLCO1C1) at the blood-brain barrier.
2008,
Pubmed
Roef,
Associations between single nucleotide polymorphisms in thyroid hormone transporter genes (MCT8, MCT10 and OATP1C1) and circulating thyroid hormones.
2013,
Pubmed
Roth,
The tricyclic antidepressant desipramine inhibits T3 import into primary neurons.
2010,
Pubmed
Sadiq,
Oxymorphone active uptake at the blood-brain barrier and population modeling of its pharmacokinetic-pharmacodynamic relationship.
2013,
Pubmed
Schinkel,
P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs.
1996,
Pubmed
Schutkowski,
Tissue-specific expression of monocarboxylate transporters during fasting in mice.
2014,
Pubmed
Soldner,
Inhibition of human microsomal PGE2 synthase-1 reduces seizure-induced increases of P-glycoprotein expression and activity at the blood-brain barrier.
2019,
Pubmed
Urayama,
Pharmacologic manipulation of lysosomal enzyme transport across the blood-brain barrier.
2016,
Pubmed
Vijay,
Role of monocarboxylate transporters in drug delivery to the brain.
2014,
Pubmed
Wilpert,
Spatiotemporal Changes of Cerebral Monocarboxylate Transporter 8 Expression.
2020,
Pubmed
Zamek-Gliszczynski,
Pharmacokinetics of 5 (and 6)-carboxy-2',7'-dichlorofluorescein and its diacetate promoiety in the liver.
2003,
Pubmed
Zeng,
Effect of phenytoin on sodium conductances in rat hippocampal CA1 pyramidal neurons.
2016,
Pubmed
