Development of multi-route physiologically-based pharmacokinetic models for ethanol in the adult, pregnant, and neonatal rat

Abstract

Biofuel blends of 10% ethanol (EtOH) and gasoline are common in the USA, and higher EtOH concentrations are being considered (15–85%). Currently, no physiologically-based pharmacokinetic (PBPK) models are available to describe the kinetics of EtOH-based biofuels. PBPK models were developed to describe life-stage differences in the kinetics of EtOH alone in adult, pregnant, and neonatal rats for inhalation, oral, and intravenous routes of exposure, using data available in the open literature. Whereas ample data exist from gavage and intravenous routes of exposure, kinetic data from inhalation exposures are limited, particularly at concentrations producing blood and target tissue concentrations associated with developmental neurotoxicity. Compared to available data, the three models reported in this paper accurately predicted the kinetics of EtOH, including the absorption, peak concentration, and clearance across multiple datasets. In general, model predictions for adult and pregnant animals matched inhalation and intravenous datasets better than gavage data. The adult model was initially better able to predict the time-course of blood concentrations than was the neonatal model. However, after accounting for age-related changes in gastric uptake using the calibrated neonate model, simulations consistently reproduced the early kinetic behavior in blood. This work provides comprehensive multi-route life-stage models of EtOH pharmacokinetics and represents a first step in development of models for use with gasoline-EtOH blends, with additional potential applicability in investigation of the pharmacokinetics of EtOH abuse, addiction, and toxicity.

Keywords::

• Ethanol
• Pharmacokinetics
• PBPK model
• Multi-route
• Life-stage

Acknowledgements

The authors thank Drs. Elaina Kenyon, Paul Schlosser, David Herr, and John Rogers for internal reviews and helpful suggestions regarding the content and editing of the manuscript.

Declaration of interest

The information in this document has been funded by the Environmental Protection Agency, in part through USEPA contract EP-C-09-006. It has been subjected to review by the National Health and Environmental Effects Research Laboratory and approved for publication. Approval doses not signify that the contents reflect the views of the Agency nor does mention of trade names or commercial products constitute endorsement or recommendation for use.