MONOCARBOXYLATE TRANSPORTERS - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 158

be transported with high affinity by both MCTs and the sodium-dependent multivita-
min transporter (SMVT) in Caco-2 cells. 73 The hypoglycemic agent nateglinide has
also been demonstrated to be transported in part by MCTs, but other significant trans-
port mechanisms exist. 74 The ineffectiveness of the anticancer drug 6-mercaptopurine
(6-MP) in the central nervous system of patients with acute lymphoblastic leukemia
has been attributed to a high rate of 6-MP efflux across the BBB by MCTs. 75
Many compounds that are derived from dietary sources can have powerful antiox-
idant properties. Some of these naturally occurring compounds, such as quercetin,
artepillin, caffeic acid, and their metabolites, produced by bacterial metabolism are
known to be transported by MCTs expressed in Caco-2 cells, and thus by inference,
across the intestinal epithelium. 76 − 79 Although many clinically relevant compounds
are transported by MCTs, a few drugs influence MCT1 gene and protein expression
but do not serve as substrates. The anti-cancer drug flutamide, used in the treatment of
prostate cancer, has been shown to cause a significant decrease in MCT1 and MCT2
mRNA expression and causes long-term deficits in lactate transport in rats exposed to
the drug during the fetal life stage. 80 Furthermore, the 2 -agonist clenbuterol, a bron-

chodilator with potent anabolic properties, was found to cause significant decreases
in MCT1 protein expression in both the soleus and extensor digitorum longus (EDL)
muscles in rats after 4 weeks of drug exposure. 81

7.4.2. Inhibitors

There is a wide range of reversible and irreversible inhibitors of monocarboxylate
transport. These inhibitors can be classified into four general categories. First, sub-
stituted aromatic monocarboxylates such as phenylpyruvate and derivatives of α -

cyanocinnamate ( α -CHC) serve as potent competitive reversible MCT inhibitors.

Although -CHC is commonly used as a MCT inhibitor, it is a more potent inhibitor

of the mitochondrial pyruvate carrier. 82 Therefore, this inhibitor blocks oxidative
phosphorylation and causes the toxic buildup of lactic acid. Second, pyrrolopyrim-
idinedione (PPD) derivatives serve as highly specific MCT inhibitors. 83 , 84 These
compounds are known to have potent immunosuppressant effects by specifically
preventing T-lymphocyte activation through inhibition of lactate transport. 83 Third,
there are amphiphilic compounds that can also serve as competitive reversible MCT
inhibitors. Compounds in this group include the anion transport inhibitors 5-nitro-
2-(3-phenylpropylamino)benzoate (NPPB) and niflumate. Additionally, the naturally
occurring flavonoids quercetin and phloretin have been shown to bind competitively
with MCTs. Aside from its antioxidant properties, quercetin also suppresses the
stress response by inhibiting the expression of heat shock proteins. 85 Phloretin has
been shown to increase membrane fluidity and inhibit the transport of many organic
acids, inorganic ions, and nonelectrolytes. 86 Finally, stilbene disulfonates such as
4,4 -diisothiocyanostilbene-2,2 -disulfonate (DIDS) and 4,4 -dibenzamidostilbene-
2,2 -disulfonate (DBDS) serve as very potent, membrane-impermeant, competitive,
and reversible inhibitors of MCTs. 87 Prolonged exposure (

α

1 hour) to DIDS, however,
can lead to irreversible inhibition due to the modification of amino groups at the cell
surface. Therefore, DBDS may be a more practical inhibitor in this category because

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