Biomedical Engineering Reference
In-Depth Information
are awaited to elucidate the relationship between genetic variation in organic cation
transporters and drug disposition and toxicities.
Main Substrate Classes (Clinically Applied) and Inhibitors
In general, the OCTs
mediate the transport of structurally diverse small hydrophilic organic cations, and
they display a broadly but not completely overlapping substrate specificity. Inter-
species differences in the function of the OCTs have also been described. OCT
substrates include the model substrate tetraethylammonium (TEA), the neurotoxin
1-methyl-4-phenylpyridinium (MPP
+
), and clinically applied drugs such as antidi-
abetics (biguanides)
664
-
blockers (acebutolol),
665
the H2-receptor antagonist cimetidine,
667
,
668
skeletal mus-
cle relaxants (e.g., vecuronium),
665
,
668
,
669
and several other endogenous compounds,
such as dopamine,
666
,
668
noradrenalin, serotonin, histamine,
666
,
667
,
670
creatinine, and
choline.
665
,
671
Moreover, OCT1 and OCT2 have been demonstrated to transport some
anionic prostanoids (i.e., prostaglandins and their derivatives), indicating that a pos-
itive charge is not an absolute prerequisite for being an OCT substrate.
526
Lately, the
tyrosine kinase inhibitor imatinib mesylate was shown to be transported into cells
by OCT1, thus confirming previous studies suggesting that influx proteins in gen-
eral (and OCT1 in particular) might play an important role in imatinib mesylate cell
accumulation and response during treatment.
672
,
673
In a group of patients affected
by chronic myeloid leukemia, the cell expression/function of OCT1 was correlated
significantly with patient response to imatinib mesylate treatment.
671
Similarly, increased accumulation and cytotoxicity of the anticancer drug oxali-
platin (but not of cisplatin or carboplatin) was reported in human OCT1 and OCT2
transfected cells, indicating that oxaliplatin is a substrate of these transporters. These
findings suggest that OCT1 and OCT2 tumor expression might be a determinant of
the anticancer activity of oxaliplatin and might contribute to its antitumor specificity.
Additional studies are needed to elucidate the role of tumor OCT expression as
a marker for selecting specific platinum-based therapies in individual patients.
675
Moreover, the consequences of the modulation of OCTs on pharmacokinetics and
anticancer activity of oxaliplatin should be explored.
Several compounds have been shown to inhibit uptake of the prototypes TEA
or MPP
antiparkinson drugs (amantadine and memantine),
665
,
666
in a competitive or noncompetitive manner, suggesting that they can in-
teract with OCTs. Cimetidine appears to produce a noncompetitive inhibition of
OCTs, whereas cisplatin has been reported to inhibit TEA uptake by mouse Oct2
competitively.
676
The antiarrhytmic procainamide is reported to inhibit OCT1 as well
as OCT2 and OCT3 efficiently; quinine and quinidine appear to alter the activity of
OCT1 and OCT2.
665
,
669
,
671
,
677
In a mammalian expression system for murine OCT2
and OCT3, several steroids (in particular,
+
-estradiol, corticosterone, deoxycorti-
costerone, papaverine, testosterone, and progesterone) were found to inhibit TEA
uptake.
678
In addiction, the HIV protease inhibitors ritonavir, saquinavir, indinavir,
and nelfinavir have been reported to be potent inhibitors but poor substrates for human
OCT1.
669
,
679
Finally, several flavonoids (such as quercetin, kaempferol, naringenin,
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