title: Application of physiologically-based pharmacokinetic modeling to explore the role of kidney transporters in renal reabsorption of perfluorooctanoic acid in the rat.
abstract: Renal elimination and the resulting clearance of perfluorooctanoic acid (PFOA) from the serum exhibit pronounced sex differences in the adult rat. The literature suggests that this is largely due to hormonally regulated expression of organic anion transporters (OATs) on the apical and basolateral membranes of the proximal tubule cells that facilitate excretion and reabsorption of PFOA from the filtrate into the blood. Previously developed PBPK models of PFOA exposure in the rat have not been parameterized to specifically account for transporter-mediated renal elimination. We developed a PBPK model for PFOA in male and female rats to explore the role of Oat1, Oat3, and Oatp1a1 in sex-specific renal reabsorption and excretion of PFOA. Descriptions of the kinetic behavior of these transporters were extrapolated from in vitro studies and the model was used to simulate time-course serum, liver, and urine data for intravenous (IV) and oral exposures in both sexes. Model predicted concentrations of PFOA in the liver, serum, and urine showed good agreement with experimental data for both male and female rats indicating that in vitro derived physiological descriptions of transporter-mediated renal reabsorption can successfully predict sex-dependent excretion of PFOA in the rat. This study supports the hypothesis that sex-specific serum half-lives for PFOA are largely driven by expression of transporters in the kidney and contribute to the development of PBPK modeling as a tool for evaluating the role of transporters in renal clearance.
authors.affiliation: Agency for Toxic Substances and Disease Registry, Division of Community Health Investigations, 4770 Buford Highway, Atlanta, GA 30341, United States; Interdisciplinary Toxicology Program, University of Georgia, 341 Pharmacy South, Athens, GA 30602, United States. Electronic address: idz7@cdc.gov.
authors.forename: Rachel Rogers
authors.initials: RR
authors.lastname: Worley
authors.affiliation: Interdisciplinary Toxicology Program, University of Georgia, 341 Pharmacy South, Athens, GA 30602, United States; Food and Drug Administration, National Center for Toxicological Research, 3900 NCTR Road, Jefferson, AR 72079, United States.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Fisher
mesh_terms: D000818:Animals; D002210:Caprylates / Q000378:metabolism*; D005260:Female; D005466:Fluorocarbons / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000502:physiology*; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism; D027361:Organic Anion Transporters / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D065608:Renal Reabsorption / Q000502:physiology*; D012727:Sex Characteristics
chemical_list: D002210:Caprylates; D005466:Fluorocarbons; D026901:Membrane Transport Proteins; D027361:Organic Anion Transporters; C023036:perfluorooctanoic acid
keywords: IVIVE; Oat1; Oat3; Oatp1a1; PBPK; PFOA