title: Absence of P-glycoprotein transport in the pharmacokinetics and toxicity of the herbicide paraquat.
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 (mdr1a(-/-)/mdr1b(-/-)) 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 µM (31.2-37.2)-respectively; 3) transepithelial permeability ratios of paraquat were the same in P-gp-expressing and nonexpressing cells (1.55 ± 0.39 and 1.39 ± 0.43, respectively); and 4) paraquat did not inhibit rhodamine-123 transport. Population pharmacokinetic modeling revealed minor differences between FVB wild-type and mdr1a(-/-)/mdr1b(-/-) 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 wild-type and mdr1a(-/-)/mdr1b(-/-) 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.
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences (S.E.L, K.S., E.S., R.D., F.C.-P, E.L.W.), Center for Environmental Health Sciences (S.E.L., F.C.-P.), Center for Biomolecular Structure and Dynamics (E.L.W.), Department of Chemistry (J.N.G., K.D.S.), University of Montana, Missoula, Montana; and Department of Pediatrics, University of Utah, Salt Lake City, Utah (C.M.T.S.).
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Lacher
authors.forename: Julia N
authors.initials: JN
authors.lastname: Gremaud
authors.forename: Kasse
authors.initials: K
authors.lastname: Skagen
authors.forename: Emily
authors.initials: E
authors.lastname: Steed
authors.forename: Rachel
authors.initials: R
authors.lastname: Dalton
authors.forename: Kent D
authors.initials: KD
authors.lastname: Sugden
authors.forename: Fernando
authors.initials: F
authors.lastname: Cardozo-Pelaez
authors.forename: Catherine M T
authors.initials: CM
authors.lastname: Sherwin
authors.forename: Erica L
authors.initials: EL
authors.lastname: Woodahl
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D005456:Fluorescent Dyes / Q000378:metabolism; D006540:Herbicides / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D049990:Membrane Transport Modulators / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D010269:Paraquat / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D010300:Parkinson Disease / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D020112:Rhodamine 123 / Q000378:metabolism; D034421:Sus scrofa; D014018:Tissue Distribution; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D005456:Fluorescent Dyes; D006540:Herbicides; D049990:Membrane Transport Modulators; D010269:Paraquat; D011994:Recombinant Proteins; D020112:Rhodamine 123; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C095122:multidrug resistance protein 3