Involvement of P-glycoprotein,Multidrug Resistance Protein 2 and Breast Cancer Resistance Protein in the Transport of Belotecan and Topotecan in Caco-2 and MDCKII Cells |
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Authors: | Hong Li Hyo-Eon Jin Wooyoung Kim Yong-Hae Han Dae-Duk Kim Suk-Jae Chung Chang-Koo Shim |
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Affiliation: | (1) National Research Laboratory for Transporters Targeted Drug Design, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, 599 Gwanangno, Gwanak-gu, Seoul, 151-742, Republic of Korea;(2) Department of Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization, Bristol-Myers Squibb R&D, Princeton, New Jersey, USA |
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Abstract: | Purpose To investigate the underlying mechanism of low bioavailabilities of the water-soluble camptothecin derivatives, belotecan
and topotecan.
Methods The bioavailability of belotecan and topotecan in rats was determined following oral administration of each drug at a dose
of 5 mg/kg body weight. The vectorial transport of each drug was measured in Caco-2 and engineered MDCK II cells.
Results The bioavailability of belotecan (11.4%) and topotecan (32.0%) in rats was increased to 61.5% and 40.8%, respectively, by
the preadministration of CsA at a dose of 40 mg/kg. Contrary to the absorptive transport, the secretory transport of these
drugs across the Caco-2 cell monolayer was concentration-dependent, saturable, and significantly inhibited by the cis presence of verapamil (a P-gp substrate), MK-571 (an MRP inhibitor), bromosulfophthalein (BSP, an MRP2 inhibitor), fumitremorgin
C (FTC, a BCRP inhibitor) and cyclosporine A (CsA, an inhibitor of P-gp and BCRP, and a substrate of P-gp) suggesting the
involvement of these transporters, which could be further confirmed in MDCKII/P-gp, MDCKII/MRP2 and MDCKII/BCRP cells.
Conclusion The involvement of secretory transporters P-gp, MRP2 and BCRP, particularly for belotecan, as well as a low passive permeability,
appears to be responsible for the low bioavailability of belotecan and topotecan.
Hong Li and Hyo-Eon Jin have contributed equally to this work. |
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Keywords: | BCRP belotecan bioavailability MRP2 P-gp topotecan |
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