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ToxSci Advance Access published online on March 15, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn054
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Tissue exposures to free and glucuronidated monobutylyphthalate in the pregnant and fetal rat following exposure to di-n-butylphthalate: Evaluation with a PBPK model

Rebecca A. Clewell{wedge},{ddagger},*, John J. Kremer{ddagger},&, Carla C. Williams{ddagger}, Jerry L. Campbell, Jr{ddagger}, Melvin E. Andersen{ddagger} and Susan J. Borghoff{ddagger},{dagger}

{wedge} The University of North Carolina, Chappell Hill, NC 27599 {ddagger} The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709 Current Addresses & John J Kremer, Ph.D., Boston Scientific Corporation, Maple Grove, MN 55311 {dagger} Susan Borghoff, Ph.D., Integrated Laboratory Systems, Inc, Research Triangle Park, NC 27707

* To whom correspondence should be addressed: Rebecca A. Clewell, The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, NC 27709, Tel: (919) 558-1307, Fax: (919) 558-1300, E-mail: rclewell{at}thehamner.org

Received November 21, 2007; revision received February 21, 2008; accepted March 9, 2008


  Abstract

Human exposure to phthalic acid diesters occurs through a variety of pathways as a result of their widespread use in plastics. Repeated doses of di-n-butyl phthalate (DBP) from GD 12-19 disrupt testosterone synthesis and male sexual development in the fetal rat. To gain a better understanding of the relationship of the target tissue (testes) dose to observed developmental effects, the pharmacokinetics of monobutyl phthalate (MBP) and its glucuronide (MBP-G) were examined in pregnant and fetal rats following single and repeated administration of DBP from GD 12–19. These data, together with results from previously published studies, were used to develop a physiologically based pharmacokinetic (PBPK) model for DBP and its metabolites in the male, pregnant and fetal rat. The model structure accounts for the major metabolic (hydrolysis, glucuronidation, oxidative metabolism) and transport processes (enterohepatic recirculation, urinary and fecal excretion, placental transfer). Extrapolation of the validated adult male rat model to gestation successfully predicts MBP and MBP-G levels in maternal plasma, placenta and urine, as well as the fetal plasma and testes. Sensitivity analysis indicates that plasma MBP kinetics are particularly sensitive to glucuronidation and enterohepatic recirculation: a decrease in the UDPGT capacity during gestation results in an increased MBP residence time, and saturation of UDPGT at the highest doses (> 100 mg/kg/day) causes a flattening out of the plasma time-course data. Oxidative metabolism plays a significant role in elimination only at low doses (<50 mg/kg DBP). Insights gained from modeling of the rat data will be used to support development of a human PBPK model for DBP.

Key Words: PBPK Model; Phthalate; DBP; Glucuronide; Gestation; Rat; Kinetics.


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