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Publication
Contribution of Organic Anion-Transporting Polypeptides 1A/1B to Doxorubicin
Uptake and Clearance.
Authors Lee HH, Leake BF, Kim RB, Ho RH
Submitted By Submitted Externally on 1/18/2017
Status Published
Journal Molecular pharmacology
Year 2017
Date Published 1/1/2017
Volume : Pages 91 : 14 - 24
PubMed Reference 27777271
Abstract The organic anion-transporting polypeptides represent an important family of
drug uptake transporters that mediate the cellular uptake of a broad range of
substrates including numerous drugs. Doxorubicin is a highly efficacious and
well-established anthracycline chemotherapeutic agent commonly used in the
treatment of a wide range of cancers. Although doxorubicin is a known substrate
for efflux transporters such as P-glycoprotein (P-gp; MDR1, ABCB1),
significantly less is known regarding its interactions with drug uptake
transporters. Here, we investigated the role of organic anion transporting
polypeptide (OATP) transporters to the disposition of doxorubicin. A recombinant
vaccinia-based method for expressing uptake transporters in HeLa cells revealed
that OATP1A2, but not OATP1B1 or OATP1B3, and the rat ortholog Oatp1a4 were
capable of significant doxorubicin uptake. Interestingly, transwell assays using
Madin-Darby canine kidney II cell line cells stably expressing specific uptake
and/or efflux transporters revealed that OATP1B1, OATP1B3, and OATP1A2, either
alone or in combination with MDR1, significantly transported doxorubicin. An
assessment of polymorphisms in SLCO1A2 revealed that four variants were
associated with significantly impaired doxorubicin transport in vitro. In vivo
doxorubicin disposition studies revealed that doxorubicin plasma area under the
curve was significantly higher (1.7-fold) in Slco1a/1b(-/-) versus wild-type
mice. The liver-to-plasma ratio of doxorubicin was significantly decreased
(2.3-fold) in Slco1a/1b2(-/-) mice and clearance was reduced by 40% compared
with wild-type mice, suggesting Oatp1b transporters are important for
doxorubicin hepatic uptake. In conclusion, we demonstrate important roles for
OATP1A/1B in transporter-mediated uptake and disposition of doxorubicin.




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