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

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. (14)C-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 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 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.

NTP‐CERHR expert panel report on the reproductive and developmental toxicity of bisphenol A

“…2.1.2.1 Absorption: In rats orally exposed to bisphenol A at doses r100 mg/kg bw, maximum bisphenol A concentrations (C max ) were generally measured in plasma within 0.083-0.75 hr following exposure (Pottenger et al, 2000;Takahashi and Oishi, 2000;Yoo et al, 2001;Domoradzki et al, 2004;Negishi et al, 2004b). At doses of 1 or 10 mg/kg bw, time to maximum bisphenol A concentration (T max ) in plasma was longer in postnatal day (PND) 21 rats (1.5-3 hr) than in PND 4 and 7 rats (0.25-0.75 hr) (Domoradzki et al, 2004).…”

“…At doses of 1 or 10 mg/kg bw, time to maximum bisphenol A concentration (T max ) in plasma was longer in postnatal day (PND) 21 rats (1.5-3 hr) than in PND 4 and 7 rats (0.25-0.75 hr) (Domoradzki et al, 2004). In a limited number of studies in which rats were subcutaneously (s.c.) dosed with up to 100 mg/kg bw bisphenol A, time (0.5-4 hours) to reach C max was longer than with oral dosing, although the findings were not always consistent (Pottenger et al, 2000;Negishi et al, 2004b).…”

“…As discussed in greater detail in Section 2.1.2.3, bisphenol A is glucuronidated in the liver and intestine, and most of the dose is absorbed as bisphenol A glucuronide following oral exposure of rats (Domoradzki et al, 2004). In ovariectomized rats gavaged with bisphenol A, bioavailability of bisphenol A was reported at 16.4% at a 10 mg/kg bw dose and 5.6% at a 100 mg/kg bw dose (Upmeier et al, 2000).…”

“…Similarly, HPLC analysis of plasma conducted 1 hr following s.c. or gavage dosing of 4 female 21-day-old Sprague-Dawley rats/group with bisphenol A revealed higher bisphenol A plasma concentrations with s.c. than with gavage dosing (Table 22) (Yamasaki et al, 2000). One study in male and female rats gavaged with 10 mg/kg bw bisphenol A demonstrated higher plasma concentrations of bisphenol A in immature animals than in adults (10.2-48.3 mg/g [mg/L] plasma at 4 days of age; 1.1-1.4 mg/g [mg/L] plasma at 7 days of age; 0.2 mg/g [mg/L] plasma at 21 days of age; and 0.024-0.063 mg/g [mg/L] plasma in adulthood) (Domoradzki et al, 2004).…”

“…dosing of quail hens (with apparently 105 lg bisphenol A), but concentrations in eggs were not quantified by study authors.] 2.1.2.2.2 Non-pregnant and non-lactating animals: Domoradzki et al (2004), examined the effects of dose and age on toxicokinetics and metabolism of bisphenol A in rats. Neonatal and adult male and female SpragueDawley rats were gavaged with 14 C-bisphenol A (B99% radiochemical purity)/non-radiolabeled bisphenol A (99.7% purity).…”