Pharmacokinetic modeling: Prediction and evaluation of route dependent dosimetry of bisphenol A in monkeys with extrapolation to humans

Journal Article · Tue Nov 15 04:00:00 EST 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/J.TAAP.2011.08.026· OSTI ID:22212558

Twaddle, Nathan C.; Vanlandingham, Michelle; Doerge, Daniel R.

A physiologically based pharmacokinetic (PBPK) model was developed for bisphenol A (BPA) in adult rhesus monkeys using intravenous (iv) and oral bolus doses of 100 {mu}g d6-BPA/kg (). This calibrated PBPK adult monkey model for BPA was then evaluated against published monkey kinetic studies with BPA. Using two versions of the adult monkey model based on monkey BPA kinetic data from and , the aglycone BPA pharmacokinetics were simulated for human oral ingestion of 5 mg d16-BPA per person (Voelkel et al., 2002). Voelkel et al. were unable to detect the aglycone BPA in plasma, but were able to detect BPA metabolites. These human model predictions of the aglycone BPA in plasma were then compared to previously published PBPK model predictions obtained by simulating the Voelkel et al. kinetic study. Our BPA human model, using two parameter sets reflecting two adult monkey studies, both predicted lower aglycone levels in human serum than the previous human BPA PBPK model predictions. BPA was metabolized at all ages of monkey (PND 5 to adult) by the gut wall and liver. However, the hepatic metabolism of BPA and systemic clearance of its phase II metabolites appear to be slower in younger monkeys than adults. The use of the current non-human primate BPA model parameters provides more confidence in predicting the aglycone BPA in serum levels in humans after oral ingestion of BPA. -- Highlights: Black-Right-Pointing-Pointer A bisphenol A (BPA) PBPK model for the infant and adult monkey was constructed. Black-Right-Pointing-Pointer The hepatic metabolic rate of BPA increased with age of the monkey. Black-Right-Pointing-Pointer The systemic clearance rate of metabolites increased with age of the monkey. Black-Right-Pointing-Pointer Gut wall metabolism of orally administered BPA was substantial across all ages of monkeys. Black-Right-Pointing-Pointer Aglycone BPA plasma concentrations were predicted in humans orally given oral doses of deuterated BPA.

• OSTI ID: 22212558
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 1 Vol. 257; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
CLEARANCE
CONCENTRATION RATIO
DOSIMETRY
EXTRAPOLATION
INFANTS
INGESTION
LIVER
MACACUS
METABOLISM
METABOLITES
SIMULATION