Pharmacokinetics of bisphenol A in humans following a single oral administration

Abstract

Background: Human exposures to bisphenol A (BPA) are widespread. The current study addresses uncertainties regarding human pharmacokinetics of BPA.

Objective: To reduce uncertainties about the metabolism and excretion of BPA in humans following oral administration.

Methods: We exposed six men and eight women to 100 μg/kg bw of deuterated BPA (d6-BPA) by oral administration and conducted blood and urine analysis over a three day period. The use of d6-BPA allowed administered d6-BPA to be distinguished from background native (unlabeled) BPA. We calculated the rate of oral absorption, serum elimination, half-life, area under the curve (AUC), urinary excretion, and metabolism to glucuronide and sulfate conjugates.

Results: Mean serum total (unconjugated and conjugated) d6-BPA Cmax of 1711 nM (390 ng/ml) was observed at Tmax of 1.1 ± 0.50h. Unconjugated d6-BPA appeared in serum within 5-20 min of dosing with a mean Cmax of 6.5 nM (1.5 ng/ml) observed at Tmax of 1.3 ± 0.52 h. Detectable blood levels of unconjugated or total d6-BPA were observed at 48 h in some subjects at concentrations near the LOD (0.001-0.002 ng/ml). The half-times for terminal elimination of total d6-BPA and unconjugated d6-BPA were 6.4 ± 2.0 h and 6.2 ± 2.6h, respectively. Recovery of total administered d6-BPA in urine was 84-109%. Most subjects (10 of 14) excreted >90% as metabolites within 24h.

Conclusions: Using more sensitive methods, our study expands the findings of other human oral pharmacokinetic studies. Conjugation reactions are rapid and nearly complete with unconjugated BPA comprising less than 1% of the total d6-BPA in blood at all times. Elimination of conjugates into urine largely occurs within 24h.

Keywords: ADME; Bioavailability; Deuterated bisphenol A; Endocrine disruptor; Excretion; Metabolism.

Figure 1. Overview of BPA metabolism

In humans, elimination is via the urine in the form of BPA or BPA conjugates, mostly BPA-G. The elimination routes in rodents include urine as well as feces. Differences between humans and rodents are attributed to different molecular weight cutoffs for biliary excretion where the molecular weight threshold is higher in humans. Also, in rodents bisphenol A conjugates can be de-conjugated in the gut and be re-circulated back to the liver (“enterohepatic circulation”). Modified from Figure 1 of Taylor et al. (Taylor and others 2011)

Figure 2. Serum Pharmacokinetics of Unconjugated and Total d6-BPA Following Oral Administration on a Cookie

A common dose (100 μg/kg bw) was dispensed onto a vanilla wafer and eaten by each of the 14 subjects after insertion of a venous catheter. Blood sampling commenced at 0.083 h (5 min) post-dosing and continued through 12 h. Single blood samples were also drawn on subsequent days by venipuncture. Unconjugated and total d6-BPA were quantified using UPLC/MS/MS as described in the Method section. Pre-dose samples contained undetectable levels of d6-BPA. The log plots shown below represent the average concentrations ± SD (n=14). The inset expands the first 2 hours.

Figure 3. Urinary Excretion of Total d6-BPA in Human Subjects

Cumulative excretion of total d6-BPA was measured after complete enzymatic hydrolysis and is expressed as the percent of d6-BPA dose administered to each subject (n = 14). The inset expands the first 6 hours. Due to anomalously low urine recoveries in subjects 4, 5, and 12 a second round of dosing was conducted and those results were used in the aggregate kinetic analysis.