Received for publication December 15, 2004.
Revised February 2, 2005.
Accepted for publication February 4, 2005.

Transport of anthelmintic benzimidazole drugs by Breast Cancer Resistance Protein (BCRP/ABCG2)

Abstract

Methylcarbamate benzimidazoles (albendazole (ABZ), fenbendazole (FBZ), and their respective sulfoxide derivatives, albendazole sulfoxide (ABZSO) and oxfendazole (OXF)) are therapeutically important anthelmintic agents with low bioavailability. We studied their in vitro interaction with the apical ATP binding cassette (ABC) drug efflux transporters, Breast cancer resistance protein (BCRP/ABCG2), P-glycoprotein (ABCB1) and MRP2 (ABCC2) using MDCKII cells transduced with human MDR1, MRP2, BCRP and murine Bcrp1 cDNAs. These ABC drug efflux transporters extrude a wide range of xenotoxins from cells in intestine, liver and other organs, thus affecting the bioavailability of many compounds. In transport experiments, ABZSO and OXF were efficiently transported by murine Bcrp1, moderately by human BCRP, but not by MDR1 or MRP2. ABZ and FBZ were not found to be Bcrp1, MRP2 or P-gp substrates in vitro. OXF was found to be a good BCRP/Bcrp1 inhibitor, with somewhat higher potency in the MDCKII-BCRP cell line. The latter results were confirmed by flow cytometry experiments demonstrating inhibition by OXF of murine Bcrp1- and human BCRP-mediated mitoxantrone transport. Further studies of interactions between OXF and known BCRP/Bcrp1 substrates will be of interest. The use of efficacious BCRP/Bcrp1 inhibitors might increase the extent and duration of systemic exposure to ABZSO and OXF, with possible therapeutically beneficial effects in extra-intestinal infections.

Key words: ABC transporters, active transport, drug efflux, drug interactions, inhibition, membrane transport, p-glycoprotein, transporters

This article has been cited by other articles:

				J. K. Lee, K. Abe, A. S. Bridges, N. J. Patel, T. J. Raub, G. M. Pollack, and K. L. R. Brouwer Sex-Dependent Disposition of Acetaminophen Sulfate and Glucuronide in the in Situ Perfused Mouse Liver Drug Metab. Dispos., September 1, 2009; 37(9): 1916 - 1921. [Abstract] [Full Text] [PDF]

				D. Zhang, K. He, N. Raghavan, L. Wang, J. Mitroka, B. D. Maxwell, R. M. Knabb, C. Frost, A. Schuster, F. Hao, et al. Comparative Metabolism of 14C-Labeled Apixaban in Mice, Rats, Rabbits, Dogs, and Humans Drug Metab. Dispos., August 1, 2009; 37(8): 1738 - 1748. [Abstract] [Full Text] [PDF]

				G. Merino, R. Real, M. F. Baro, L. Gonzalez-Lobato, J. G. Prieto, A. I. Alvarez, and M. M. Marques Natural Allelic Variants of Bovine ATP-Binding Cassette Transporter ABCG2: Increased Activity of the Ser581 Variant and Development of Tools for the Discovery of New ABCG2 Inhibitors Drug Metab. Dispos., January 1, 2009; 37(1): 5 - 9. [Abstract] [Full Text] [PDF]

				C. E. Garner, E. Solon, C.-M. Lai, J. Lin, G. Luo, K. Jones, J. Duan, C. P. Decicco, T. Maduskuie, S. E. Mercer, et al. Role of P-Glycoprotein and the Intestine in the Excretion of DPC 333 [(2R)-2-{(3R)-3-Amino-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxopyrrolidin-1-yl}-N-hydroxy-4-methylpentanamide] in Rodents Drug Metab. Dispos., June 1, 2008; 36(6): 1102 - 1110. [Abstract] [Full Text] [PDF]

				B. Sarkadi, L. Homolya, G. Szakacs, and A. Varadi Human Multidrug Resistance ABCB and ABCG Transporters: Participation in a Chemoimmunity Defense System. Physiol Rev, October 1, 2006; 86(4): 1179 - 1236. [Abstract] [Full Text] [PDF]

				A. E.v. Herwaarden, E. Wagenaar, B. Karnekamp, G. Merino, J. W. Jonker, and A. H. Schinkel Breast cancer resistance protein (Bcrp1/Abcg2) reduces systemic exposure of the dietary carcinogens aflatoxin B1, IQ and Trp-P-1 but also mediates their secretion into breast milk Carcinogenesis, January 1, 2006; 27(1): 123 - 130. [Abstract] [Full Text] [PDF]