title: Pharmacokinetic modeling: prediction and evaluation of route dependent dosimetry of bisphenol A in monkeys with extrapolation to humans.
abstract: 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 μg d6-BPA/kg (Doerge et al., 2010). 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 Doerge et al. (2010) and Taylor et al. (2011), the aglycone BPA pharmacokinetics were simulated for human oral ingestion of 5 mg d16-BPA per person (Völkel et al., 2002). Völkel 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 Völkel 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.
authors.affiliation: Food & Drug Administration, National Center for Toxicological Research, Division of Biochemical Toxicology , 3900 NCTR Road, Jefferson, AR 72079, USA. jeffrey.fisher@fda.hhs.gov
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Fisher
authors.forename: Nathan C
authors.initials: NC
authors.lastname: Twaddle
authors.forename: Michelle
authors.initials: M
authors.lastname: Vanlandingham
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Doerge
mesh_terms: D000284:Administration, Oral; D000367:Age Factors; D000818:Animals; D001559:Benzhydryl Compounds; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D007421:Intestine, Small / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D008954:Models, Biological; D010636:Phenols / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D010636:Phenols; C006780:bisphenol A; D000098826:Bisphenol A Compounds