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ToxSci Advance Access originally published online on December 22, 2003
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Toxicological Sciences 77, 230-242 (2004)
Copyright © 2004 by the Society of Toxicology

BIOTRANFORMATION AND TOXICOKINETICS

Age and Dose Dependency of the Pharmacokinetics and Metabolism of Bisphenol A in Neonatal Sprague-Dawley Rats Following Oral Administration

J. Y. Domoradzki*,1, C. M. Thornton*, L. H. Pottenger*, S. C. Hansen*, T. L. Card*, D. A. Markham*, M. D. Dryzga*, R. N. Shiotsuka{dagger} and J. M. Waechter, Jr.*

* Toxicology and Environmental Research and Consulting, The Dow Chemical Company, Midland, Michigan 48674, and {dagger} Bayer CropScience LP, Stillwell, Kansas 66085

ABSTRACT

Previous studies demonstrated the rapid clearance of bisphenol A (BPA) from blood following oral administration to adult rats with the principal metabolite being BPA-monoglucuronide (BPA-glucuronide). Since the ontogeny of glucuronyl transferases (GT) differs with age, the pharmacokinetics of BPA were studied in neonatal animals. 14C-BPA was administered via gavage at 1 or 10 mg/kg body weight to rats at postnatal day (pnd) 4, pnd 7, pnd 21, or to 11 week old adult rats (10 mg/kg dose only). Blood (neonates and adults) and selected tissues (neonates) were collected at 0.25, 0.75, 1.5, 3, 6, 12, 18, and 24 h postdosing. BPA and BPA-glucuronide in the plasma were quantified by high-performance liquid chromatography; radioactivity in the plasma and tissues was quantified by liquid scintillation spectrometry. The data indicate that neonatal rats at all three ages metabolized BPA to BPA-glucuronide, although an age dependency in the number and concentration of plasma metabolites was observed, consistent with the ontogeny of GT. BPA-glucuronide and BPA concentrations in the plasma were greater in neonates than in adults, except at 24 h postdosing, suggesting an immaturity in the development of hepatic excretory function in neonatal rats. Nevertheless, the half-lives for the elimination of BPA-glucuronide in plasma were more rapid in neonatal animals than in adults, likely due to reduced microflora ß-glucuronidase activity and an absence of enterohepatic recirculation. A dose dependency in the metabolism and pharmacokinetics of BPA administered to neonates was also observed with nearly complete metabolism of BPA to BPA-glucuronide (94–100% of the plasma radioactivity) at a dose of 1 mg/kg. This was in contrast to finding up to 13 different plasma metabolites observed at the 10 mg/kg dose. These data indicate that, from early in neonatal life through pnd 21, there is sufficient GT activity in rats to efficiently metabolize BPA to its nonestrogenic metabolite at low doses.

Key Words: bisphenol A; BPA-glucuronide; pharmacokinetics; rats; neonates.


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