Biomedical Engineering Reference
In-Depth Information
isoquercitrin, spiraeoside, and others) have been shown to inhibit OCT2-mediated
transport in vitro.
680
Pharmacological and Toxicological Function
The pharmacological and toxicolog-
ical roles of OCT1-3 have been investigated in vivo using knockout mice gener-
ated for all three organic cation transporters.
681
-
683
Oct1
(
−
/
−
)
, Oct2
(
−
/
−
)
, Orct3
(
−
/
−
)
,
and Oct1/2
(
−
/
−
)
mice are viable, fertile and do not display any obvious physiologi-
cal defect, but present altered pharmacokinetics of substrate organic cations. In Oct
1
(
−
/
−
)
mice accumulation of the model OCT1 substrate TEA (tetraethylammonium)
in liver was significantly lower than in wild-type mice after intravenous adminis-
tration, whereas direct intestinal excretion of TEA was about twofold reduced.
681
Similarly, decreased liver accumulation but no difference in intestinal secretion was
found in Oct1
(
−
/
−
)
mice for the neurotoxin 1-methyl-4-phenylpyridium (MPP
+
) and
[
131
I]metaiodobenzylguanidine (MIBG), an anticancer drug clinically used in detec-
tion and treatment of tumors of neuroadrenergic origin, such as neuroblastoma and
pheochromocytoma.
684
These findings supported the idea that OCT1 can affect the
liver distribution of substrate drugs. Extrapolating to humans, modulation of OCT1
expression and/or activity might have clinically important consequences in drug ther-
apy. Reduced liver uptake of drugs may result in reduction of efficacy for drugs that
have the target or undergo to metabolic activation in the liver, but it can also be posi-
tive for limiting the toxicity of hepatotoxic drugs. Indeed, Wang et al. demonstrated
that Oct1 affects the distribution of the biguanide metformin and plays a key role
in biguanide-induced lactic acidosis, a life-threatening adverse effect of biguanides.
Distribution in liver and small intestine of the intravenously administered metformin,
as well as the blood lactate concentration, were decreased significantly in Oct1
(
−
/
−
)
compared with wild-type mice.
664
,
685
In all these animal experiments no clear dif-
ference was found in the renal distribution and elimination of the OCT1 substrate
compounds tested, probably due to the shift from hepatobiliary toward renal elimina-
tion and to the functional redundancy of OCT1 with OCT2 in mice.
664
,
681
Therefore,
the impact of OCTs activity on renal distribution of substrates was elucidated by
generating Oct2 single- and Oct1/2 double-knockout mice. Using this model, Jonker
et al. reported that although the absence of Oct2 had little effect on the renal distribu-
tion of substrate compounds (such as TEA), the concomitant deficiency of Oct1 and
Oct2 in mice resulted in a complete abolishment of the renal secretion of TEA.
686
By extrapolating from rodents to humans (where only OCT2 and not OCT1 has been
reported to be expressed in the kidney), it can be expected that OCT2 deficiency in
humans may result in altered renal elimination and consequently, increased exposure
to some drugs.
The pharmacological and physiological functions of Oct3 were partly elucidated
by generation of Oct3 knockout mice.
683
Oct3 knockout mice do not present obvious
physiological or neural phenotype and also no imbalance of monoamine neurotrans-
mitters (noradrenalin and dopamine). However, Oct3
(
−
/
−
)
mice showed a significant
reduction in heart uptake of MPP
+
, a neurotoxin involved in the etiology of Parkin-
son's disease, suggesting that Oct3 is an essential component in vivo for the trans-
port activity of the extraneuronal monoamine clearance system named uptake-2.
683
Search WWH ::
Custom Search