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ToxSci Advance Access published online on April 15, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg040
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received November 14, 2002; accepted January 7, 2003
© 2003 Society of Toxicology

Biotransformation and Toxicokinetics

Disposition of Low Dose of 14C-Bisphenol A (BPA) in Male Rats and Its Main Biliary Excretion as BPA Glucuronide at Two Doses, 0.1 and 100 mg/kg: Isolation and Characterization of BPA Glucuronide from Rat Bile

Hideo Kurebayashi 1*, Hiroshi Betsui 1, Yasuo Ohno 1

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

* To whom correspondence should be addressed. E-mail: kurebaya{at}nihs.go.jp.


  Abstract

Bisphenol A (BPA) is a weak xenoestrogen mass-produced with potential human exposure. The disposition of bisphenol A (BPA) in male Fischer-344 (F-344) 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 and the fecal excretion were the main excretion routes in rats irrespective of dose and administration route. The biliary excretion during 6 h was 58-66% after intravenous (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, t1/2{beta} = 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(0-6h), AUC(0-48h) and AUCinf of 14C-BPA-derived radioactivity, were 34, 118 and 192 ng-eq·h/mL for iv dose and 18, 102 and 185 ng-eq·h/mL for oral dose, respectively. The oral bioavailability of F(0-6h), F(0-48h) 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.

bisphenol A, xenoestrogens, absorption, excretion, biliary metabolite, BPA glucuronide, enterohepatic circulation, rats .


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