Absence of P-glycoprotein transport in the pharmacokinetics and toxicity of the herbicide paraquats

Sarah E. Lacher, Julia N. Gremaud, Kasse Skagen, Emily Steed, Rachel Dalton, Kent D. Sugden, Fernando Cardozo-Pelaez, Catherine M.T. Sherwin, Erica L. Woodahl

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15 Scopus citations

Abstract

Genetic variation in the multidrug resistance gene ABCB1, which encodes the efflux transporter P-glycoprotein (P-gp), has been associated with Parkinson disease. Our goal was to investigate P-gp transport of paraquat, a Parkinson-associated neurotoxicant. We used in vitro transport models of ATPase activity, xenobiotic-induced cytotoxicity, transepithelial permeability, and rhodamine-123 inhibition. We also measured paraquat pharmacokinetics and brain distribution in Friend leukemia virus B-type (FVB) wild-type and P-gp-deficient (mdr1a2/2/ mdr1b2/2) mice following 10, 25, 50, and 100 mg/kg oral doses. In vitro data showed that: 1) paraquat failed to stimulate ATPase activity; 2) resistance to paraquat-induced cytotoxicity was unchanged in P-gp-expressing cells in the absence or presence of P-gp inhibitors GF120918 [N-(4-[2-(1,2,3,4-tetrahydro-6,7- dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10- dihydro-5-methoxy- 9-oxo-4-acridine carboxamide] and verapamil-37.0 [95% confidence interval (CI): 33.2-41.4], 46.2 (42.5-50.2), and 34.1 mM (31.2-37.2)-respectively; 3) transepithelial permeability ratios of paraquat were the same in P-gp-expressing and nonexpressing cells (1.55 6 0.39 and 1.39 6 0.43, respectively); and 4) paraquat did not inhibit rhodamine-123 transport. Population pharmacokinetic modeling revealed minor differences between FVB wild-type and mdr1a2/2/mdr1b2/2 mice: clearances of 0.47 [95% confidence interval (CI): 0.42-0.52] and 0.78 l/h (0.58-0.98), respectively, and volume of distributions of 1.77 (95% CI: 1.50-2.04) and 3.36 liters (2.39-4.33), respectively; however, the change in clearance was in the opposite direction of what would be expected. It is noteworthy that paraquat brain-to-plasma partitioning ratios and total brain accumulation were the same across doses between FVB wildtype and mdr1a2/2/mdr1b2/2 mice. These studies indicate that paraquat is not a P-gp substrate. Therefore, the association between ABCB1 pharmacogenomics and Parkinson disease is not attributed to alterations in paraquat transport.

Original languageEnglish (US)
Pages (from-to)336-345
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume348
Issue number2
DOIs
StatePublished - Feb 2014
Externally publishedYes

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