MONOCARBOXYLATE TRANSPORTERS - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 157

Multiple monocarboxylates have been tested as substrates for MCT1-4 (Table
7.1). While MCT1 has a moderate affinity for lactate and pyruvate, it appears to have
a slightly higher affinity for pyruvate in all species that have been studied. Few data
are available on MCT3 kinetics, but the chicken isoform appears to have a similar
affinity for lactate as MCT1. 54 In both rat and human, MCT4 is a low-affinity lactate
transporter ( K m 28 to 34 mM), where its proposed function is to extrude lactate from
highly glycolytic cells, such as skeletal muscle fibers and astrocytes. 22 , 55
In contrast to MCT1-4, SMCT1 transports monocarboxylates with a very high
affinity, with butyrate being the preferred substrate. 10 Another unique property of
SMCT1 is that it has similar transport affinities for both L- and D-lactate. Although
SMCT1 and SMCT2 transport similar substrates, the K m values for SMCT2 could not
be computed, due to the inability to saturate the transporter. 12 In addition to lactate,
pyruvate, and SCFA, both SMCT1 and MCT1 contribute to the uptake of the water-
soluble B-complex vitamin nicotinic acid in the intestinal epithelium. 56 , 57 Addition-
ally, SMCT1 was originally identified as a iodide transporter, but recent studies suggest
that the transporter acts as an iodide channel that is gated by monocarboxylates. 58 , 59

Clinically Relevant Drugs Although drugs administered orally can enter the body
through passive diffusion in the intestinal tract, transport involving specific membrane
carriers in the intestinal epithelium may contribute significantly. The expression of
MCTs in the human gut and elsewhere throughout the body makes this carrier family
particularly important for the enhanced uptake of exogenous and clinically relevant
substrates from the gut lumen and for their subsequent delivery into target tissues. Ad-
ditionally, the presence of MCTs in many barrier systems, including the blood-brain
barrier, blood-testis barrier, and blood-placental barrier, provide a means by which
drugs can be targeted to tissues where passive diffusion is unlikely to occur. Exoge-
nous substrates that are transported via MCTs are typically anions of small, weak,
monovalent organic acids that are either hydrophobic or hydrophilic. 4 Facilitated dif-
fusion of weak organic acids such as acetate, propionate, benzoate, and nicotinate
have been demonstrated both in in vitro and in vivo and are likely to be mediated by
MCTs. 60 − 63
Although it has been proposed that nonsteroidal anti-inflammatory compounds
(NSAIs) such as salicylic acid and ibuprofen are transported by MCTs, 64 , 65 studies
in a human trophoblast cell line show that MCT-mediated transport of these com-
pounds is unlikely. 66 However, even though NSAIs may not be transported, these
compounds appear to interact with MCTs and inhibit the transport of endogenous
monocarboxylates. Several -lactam antibiotics, including phenethicillin, propicillin,

and carindacillin, are reportedly transported by MCTs. 67 Cellular uptake of another

-lactam drug, cefdinir, is in part by MCT activity. 68 Transport of the 3-hydroxy-3-
methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors simvastatin and ator-
vastatin across the blood-brain barrier (BBB) is also mediated by MCTs. 69 − 71 The
use of valproic acid, an antiepileptic agent, during pregnancy has been associated
with causing fetal malformations, and its transport across the intestinal epithelium and
blood-placental barrier is hypothesized to occur via MCTs. 72 Additionally, XP13512,
a recently developed gabapentin prodrug used for treatment of seizures, is reported to