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.
Footnotes
- Received June 7, 2016.
- Accepted October 18, 2016.
This work was supported by Hyundai Hope on Wheels, the National Institutes of Health National Institute of General Medical Sciences [Grant R01 GM099924], the National Cancer Institute [Grant CA68485], National Institute of Diabetes and Digestive and Kidney Diseases [Grants DK20593, DK58404, DK59637], and National Eye Institute [Grant EY08126]; Cell Imaging Shared Resource (CISR) at Vanderbilt University Medical Center; and the Canadian Institutes of Health Research [Grants MOP-8975 and DSEN-PREVENT FRN-117588].
- Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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