Disposition of a low dose of 14C-bisphenol A in male rats and its main biliary excretion as BPA glucuronide.
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, t1/2beta = 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.
Kurebayashi
Hideo
H
Division of Pharmacology, National Institute of Health Sciences, Kamiyoga 1-18-1, Setagaya, Tokyo 158-8501, Japan. kurebaya@nihs.go.jp
Betsui
Hiroshi
H
Ohno
Yasuo
Y
D000818:Animals; D019540:Area Under Curve; D001559:Benzhydryl Compounds; D001646:Bile / Q000378:metabolism*; D001711:Biotransformation; D001798:Blood Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004968:Estrogens, Non-Steroidal / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D005243:Feces / Q000737:chemistry; D005260:Female; D020719:Glucuronides / Q000378:metabolism; D006207:Half-Life; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010636:Phenols / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D011485:Protein Binding; D051381:Rats; D011916:Rats, Inbred F344; D021241:Spectrometry, Mass, Electrospray Ionization; D014018:Tissue Distribution; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D001798:Blood Proteins; D004968:Estrogens, Non-Steroidal; D020719:Glucuronides; D010636:Phenols; C006780:bisphenol A; D000098826:Bisphenol A Compounds