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the oral bioavailability was much lower in mice
(2.8%) than in rats (22 76%). As indinavir is a
CONCLUSIONS
substrate for CYP3A isozymes and efflux trans-
porters MDR1, MRP1, and MPR2,18 which are
A serial blood sampling methodology in mice has
significantly expressed in the small intestine and
been developed and employed for the pharmaco-
liver, the species differences in activities and levels
kinetic and bioavailability studies of indinavir
of these enzymes and transporters could lead to a
and rosuvastatin, two structurally diverse drugs
different first pass effect and therefore a difference
with distinctly different physicochemical and
in oral bioavailability. Additionally, this discre-
pharmacokinetic properties. The concentration
pancy in oral bioavailability could be attributed to
time profiles and pharmacokinetic parameter
the formulation effects since different oral dosing
values from serial blood sampling are in good
solutions were used: cyclodextrin-based solutions
agreement with those from discrete sampling
in mice and carboxymethylcellulose-based formu-
following both oral and intravenous administra-
lations in rats. The same cyclodextrin-based
tions of each compound in mice. Compared to
formulation was used for both intravenous and
discrete sampling in mice, serial blood sampling
oral administrations of indinavir in mice in order to
offers a remarkable reduction in animal and
cancel out the effects of the formulation on the
compound usage due to a drastically reduced
clearance mechanism of the drug in different
number of animals, a significant increase in
dosing routes. The pharmacokinetic profiles of
throughput because of considerably decreased
rosuvastatin in mice from this study are similar to
labor and time required for animal dosing, and an
those in rats.19 A secondary peak is observed in
overall improvement in pharmacokinetic data
the plasma concentration time curves following
quality owing to the reduced animal to animal
oral administrations of rosuvastatin to mice from
variability and dosing related error. In addition,
both the serial and discrete sampling methods as
serial blood sampling in mice is more humane
shown in Figure 2b, which is consistent with the
without the need to euthanizing a large number of
observations in rats.19 This is most likely due to
animals. Compared to serial blood sampling in
enterohepatic recirculation as 55% of the orally
rats, serial blood sampling in mice provides
dosed rosuvastatin is excreted in the bile in rats. A
significant cost savings thanks to a much smaller
glucuronide conjugate of rosuvastatin was
body size of mouse and therefore much less
detected in the mouse plasma samples, suggesting
compound required for animal dosing. The serial
biliary recycling of both the unchanged and
blood sampling in mice is especially useful and
conjugated compounds as rosuvastatin is a sub-
therefore recommended for routine first-tier
strate for several human OATP and NTCP hepatic
pharmacokinetic screens of discovery compounds,
uptake transporters and a substrate for a few
where rats are traditionally used.
major hepatic canalicular efflux transporters
including MDR1, MRP2, and BCRP. In addition
to a possible substrate for rodent hepatic canali- ACKNOWLEDGMENTS
cular transporters Mrp2 and Bcrp for the glucur-
onide conjugate to be excreted from hepatocytes We would like to thank Risa Batta and Carlos
into bile, it is likely that the glucuronide conjugate Cotto for their assistance in animal studies.
DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 5, MAY 2009
1884 PENG ET AL.
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JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 5, MAY 2009 DOI 10.1002/jps
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