Biomedical Engineering Reference
In-Depth Information
bile, are more toxic in newborn than in adult rats. For example, the following ratios of
the LD
50
of drugs in adults over those in newborn rats demonstrate increased toxicity.
Probenecid is 2.8 times more toxic in newborn than in adult rats; indocyanine green,
3.3; iopanoic acid, 3.8; digoxin, 3.8; digitoxin, 4.6; colchicine, 21; and ouabain, 40
times.
6
,
7
These observations suggest that the increased sensitivity of newborn rats to
these chemicals may be due to immaturity of their hepatic excretory mechanisms.
Because ouabain is 40 times more toxic in newborn than in adult rats,
6
,
7
is not
biotransformed prior to its excretion,
8
,
9
and is excreted from the body almost entirely
into bile,
8
it is an ideal prototype to use to determine whether the hepatic excretory
mechanism is immature in newborns.
6
The toxicity of ouabain decreased gradually
in rats from 3 to 12 days of age, with a marked decrease in toxicity observed between
12 and 21 days of age. After 30 days of age, the toxicity of ouabain was relatively
constant. Ouabain was removed very slowly from the plasma of 7-day-old rats, with a
half-time of 30 minutes compared to a half-life in an adult of approximately 5 minutes.
The reason for this longer half-life of ouabain in newborn rats is the inability of its
liver to remove ouabain from the plasma. The concentration of ouabain in the liver
of an adult rat reaches 50 times that of plasma, whereas the liver of newborns cannot
concentrate ouabain at all.
6
Ouabain uptake into hepatocytes isolated from 12-day-old
rats is much slower than hepatocytes isolated from adult rats.
10
The ability of liver to
extract ouabain from plasma and concentrate it in liver develops concurrently with the
decrease in toxicity. It appears that this inability of immature liver to extract ouabain
from the plasma and to excrete it into bile results in a prolonged high concentration
of ouabain in plasma, which is associated with a higher toxicity.
6
Lower hepatic removal rates in newborn rats have also been demonstrated for or-
ganic acids. For example, sulfobromophthalein (BSP) and indocyanine green (ICG)
are extracted from plasma and excreted into bile less efficiently in newborn than in
adult rats.
11
This difference is not as striking as that observed with ouabain, but the
time course of development of increasing clearance of the organic acids parallels that
observed with ouabain. Decreased clearance of BSP in newborns does not appear to
be due to a decreased conjugation of BSP, as similar results are obtained when the
conjugate (BSP-glutathione) is administered.
11
It has also been demonstrated that the
increased toxicity of colchicine in newborn rats is also due largely to the immatu-
rity of hepatic excretory function.
12
Whereas the immaturity in hepatic excretion of
ouabain in newborns appears to be in the transfer of ouabain from plasma to liver, for
colchicine. it is the transfer from liver to bile.
12
,
13
Biliary excretion is not mature in newborn rats,
7
,
14
dogs, rabbits,
14
and guinea
pigs.
15
Indirect evidence indicates that newborn humans also have a decreased capac-
ity to excrete foreign compounds into bile.
16
20.2.2. Hepatic Uptake
There are a number of transporters in liver responsible for the uptake and efflux of
chemicals (Figure 20.1). As noted in earlier chapters, the organic anion-transporting
polypeptide (Oatp) is an important family of uptake transporters, consisting of 15
transporters in mice.
17
The uptake transporter expressed most specifically in liver is
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