Biomedical Engineering Reference
In-Depth Information
2.6. ANIMAL MODELS
Targeted genetic disruption of the organic cation transporters in mice (i.e., OCT
knockout mice) provided the first direct evidence of the significance of organic cation
transporters to drug disposition in vivo.
2.6.1. Oct1 Knockout Mice
/
Oct
- knockout mice were shown to be viable and fertile, showing no obvious
physiological abnormalities compared with their wild-type littermates, suggesting that
Oct1 is dispensible for normal physiology.
64
However, significant differences were ob-
served in the disposition of organic cations in these mice. For example, when admini-
stered the typical organic cation, TEA,
Oct
1
-
- mice showed significantly (ap-
proximately fivefold) reduced uptake of TEA into the liver, the site of highest OCT1
expression. Biliary excretion of TEA was 2.5-fold lower in
Oct
-
/
1
- mice, which
was explained by the reduced hepatic uptake of TEA. Additionally, direct intesti-
nal excretion of TEA was reduced by approximately 50%. Renal excretion of TEA
was paradoxically increased (
-
/
1
∼
50%) in
Oct
-
/
- mice; however, this was ex-
1
plained by the lack of OCT1 in the liver of
Oct
- mice; that is, decreased
hepatic uptake of TEA in these mice resulted in increased availability to the kid-
ney for renal excretion. Further, the coexpression of Oct1 and Oct2 in rodent kid-
ney may have led to a confounding effect of Oct2 activity in
Oct
-
/
1
-
/
- mouse
1
kidney.
In addition to the pharmacokinetic differences observed for TEA,
Oct
- mice
showed similar decreases in hepatic uptake of other OCT1 substrates, including the
neurotoxin MPP
+
(
-
/
1
75%
reduced).
64
Cimetidine, an OCT1 inhibitor (but not a substrate), did not show signif-
icant differences in hepatic uptake in
Oct
∼
60% reduced) and
meta
-iodobenzylguanidine (MIBG) (
∼
- mice compared with wild-type mice.
Similar results were found after intravenous injection of [
14
C]choline, which is an
Oct1 substrate; however, it was suggested that rapid metabolism of the radiolabeled
compound to species that are not Oct1 substrates, as well as redundancy (i.e., other
transporters capable of transporting choline), may have masked any possible effect
of Oct1 on the pharmacokinetics of this compound.
Further studies of
Oct
-
/
1
- mice have focused on the antidiabetic drug met-
formin, which exerts its pharmacological effects in the liver.
Oct
-
/
1
- mice showed
a greater than 30-fold decrease in metformin uptake into liver compared with wild-
type littermates.
65
Further studies investigated the role of Oct1 in the development
of metformin-induced lactic acidosis, a leading toxicity from this drug. A signifi-
cant increase in serum lactic acid concentration was observed after administration
of metformin to wild-type mice, but only slight elevations in serum lactate were
seen in
Oct
-
/
1
- mice, despite similar pharmacokinetic profiles between genotype
groups.
66
Taken together, these results suggest that Oct1-mediated metformin trans-
port is a limiting step in metformin uptake into liver, and that the lactic acido-
sis induced by metformin is related to the availability of the drug to this target
organ.
-
/
1
Search WWH ::
Custom Search