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ToxSci Advance Access originally published online on April 15, 2003
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Toxicological Sciences 73, 17-25 (2003)
Copyright © 2003 by the Society of Toxicology

BIOTRANSFORMATION AND TOXICOKINETICS

Disposition of a Low Dose of 14C-Bisphenol A in Male Rats and Its Main Biliary Excretion as BPA Glucuronide

Hideo Kurebayashi1, Hiroshi Betsui and Yasuo Ohno

Division of Pharmacology, National Institute of Health Sciences, Kamiyoga 1-18-1, Setagaya, Tokyo 158-8501, Japan

Bisphenol A (BPA) is a weak xenoestrogen mass-produced with potential human exposure. The disposition of bisphenol A in male Fischer-344 (F344) rats dosed orally (100 or 0.10 mg/kg) or intravenously (0.10 mg/kg) was determined. Smaller amounts of the dose appeared in the urine. The main excretion route was feces in rats irrespective of dose and administration route. The biliary excretion during 6 h was 58–66% after iv dosing and 45–50% after oral dosing at 0.10 mg 14C-BPA/kg. Toxicokinetic parameters obtained from 14C-BPA-derived radioactivity in blood were the terminal elimination half-life, t1/2ß = 39.5 h, and total body clearance, CLtot = 0.52 l/h/kg after iv dosing of 0.10 mg 14C-BPA/kg to male rats. The blood concentration reached its maximum of 5.5 ng-eq/ml at 0.38 h after oral dose. AUC(0–6 h), AUC(0–48 h), and AUCinf of 14C-BPA-derived radioactivity, were 34, 118, and 192 ng-eqh/ml for the iv dose and 18, 102, and 185 ng-eqh/ml for the oral dose, respectively. The oral bioavailability of F(0–6 h), F(0–48 h), and Finf were 0.54, 0.86, and 0.97, respectively. The 14C-BPA-derived radioactivity was strongly bound to plasma protein (free fraction, fu = 0.046) and preferentially distributed to the plasma with a blood/plasma ratio of 0.67. From the bile of male rats orally dosed at 100 mg/kg, we have isolated and characterized BPA glucuronide (BPA-gluc) by ESI/MS, 1H and 13C NMR spectroscopy. HPLC analysis showed that BPA-gluc was the predominant metabolite in bile and urine. Unchanged BPA was mostly detected in feces. These results suggest that BPA is mainly metabolized to BPA-gluc and excreted into feces through the bile and subject to enterohepatic circulation in rats irrespective of dose and administration route.

Key Words: bisphenol A; xenoestrogens; absorption; excretion; biliary metabolite; BPA glucuronide; enterohepatic circulation; rats.


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