CLINICAL RELEVANCE: DRUG–DRUG INTERACTION,PHARMACOKINETICS,PHARMACODYNAMICS, AND TOXICITY - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 804

inhibitors (e.g., simvastatin, lovastatin, pravastatin, atorvastatin) at the blood-brain
barrier. 820 - 822 MCT2 has been found to transport a wide range of monocarboxy-
lates with substantially higher affinity than MCT1, in particular for pyruvate, 823 , 824
whereas MCT4 displayed lower affinity for most MCT1 substrates. 825 , 826 To date, the
substrate specificity of the other MCT isoforms has not been described fully, with the
exceptions of T-type-amino acid transporter 1 (TAT-1), which appears to transport
aromatic amino acids (phenylalanine, tyrosine, tryptophan, L-dopa), and of MCT8,
which is reported to transport the thyroid hormones T4 and T3. 827 , 828

Inhibitors (Competitive and Noncompetitive) Thus far, several MCT1 inhibitors
have been described, but none of them is specific. MCT1 inhibitors can be divided
into several groups: The first is composed of substituted bulky or aromatic monocar-
boxylates (including 2-oxo-4-methylpentanoate and phenylpyruvate) and cyanocin-
namate derivatives [e.g., -cyano-4-hydrocinnamate (CHC)] that act as competitive

inhibitors. The second group consists of amphiphilic compounds with different struc-
tures that also inhibit the anion exchanger AE1 and other membrane transporters.
This group includes bioflavonoids, such as phloretin and quercetin, and anion trans-
port inhibitors such as niflumic acid and 5-nitro-2-(3-phenyl-propylamino)benzoate
(NPPB).
Stilbenedisulfonates [e.g., 4,4 -diisothiocyanostilbene-2,2 -disulfonate (DIDS),
4,4 -dibenzamidostilbene-2,2 -disulfonate (DBDS)] are reversible weak inhibitors of
MCT1, although on prolonged exposure, DBDS appears to be able to block irre-
versibly MCT1 activity. 984 Other irreversible inhibitors are a broad range of amino
reagents (e.g., phenylglyoxal, pyridoxal phosphate) and the organomercurial thiol
reagent p -chloromercuribenzene sulfonate (pCMBS). 814 , 827 MCT2 is more sensitive
to inhibition by a range of MCT blockers, including CHC, DBDS, and DIDS, but is
insensitive to pCMBS. 823 , 824 , 829 MCT3 is reported to be insensitive to CHC, p-CMBS,
and phloretin. 830 MCT4 exhibits less affinity for most inhibitors than MCT1 and is
reported to be insensitive to DIDS. 826

Inducers Several studies suggested that in human muscles the lactate/H + transport
capacity and MCT expression could be enhanced by training. In one study, 7 days
of bicycle training increased the content of MCT1 in the vastus lateralis muscle with
an increase in the femoral venous lactate concentration during exercise. 985 In another
study, high-intensity knee-extensor exercise was reported to increase the MCT1 and
MCT4 content by 76 and 36%, respectively, with an increase in sarcolemmal trans-
port of lactate measured in vesicles prepared from muscle tissue obtained by needle
biopsies. 831 Subsequently, in another study, lon-gterm leg cycle endurance training
has been associated with an increase in MCT1 and MCT4 in the human vastus lateralis
muscle. 832 Also, MCTs have been reported to be rapidly up-regulated by exercise. 833
Indeed, in human muscles, MCT1 and MCT4 proteins were increased 2 and 4 days af-
ter a prolonged exercise bout. 834 This suggests that up-regulation of MCT1 and MCT4
involves both posttranscriptional and transcriptional mechanisms. Conversely, lactate
transport capacity is reduced and MCTs are down-regulated after denervation of mus-
cle or spinal injury. 835 - 837 Moreover, in rat heart, MCT1 is increased after ligation
of a branch of the left coronary artery, whereas in rats with streptozotocin-induced