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ToxSci Advance Access published online on December 22, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfh054
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received July 9, 2003; accepted October 20, 2003
© 2003 Society of Toxicology

Biotransformation 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 1, L. H. Pottenger 1, S. C. Hansen 1, T. L. Card 1, D. A. Markham 1, M. D. Dryzga 1, R.N. Shiotsuka 2, and J. M. Waechter Jr.1

1 Toxicology & Environmental Research and Consulting, The Dow Chemical Company, Midland, Michigan
2 Bayer CropScience LP, Stillwell, Kansas

* To whom correspondence should be addressed. E-mail: jdomoradzki{at}dow.com .


  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 was studied in neonatal animals. 14C-BPA was administered via gavage at 1 or 10 mg/kg bw to rats at post-natal day (pnd) 4, pnd 7, pnd 21, and 11-week old adults (10 mg/kg dose only). Blood (neonates and adult) and selected tissues (neonates) were collected at 0.25, 0.75, 1.5, 3, 6, 12, 18 and 24 h post-dosing. 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 of neonates were greater than in adults, except at 24 h post-dosing, 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 {beta}-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 10 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 non-estrogenic metabolite at low doses.

Key Words: Bisphenol A, BPA-glucuronide, pharmacokinetics, rats, neonates .


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