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.

Toxicological outcomes in rats exposed to inhaled ethanol during gestation

“…Review of the individual behaviors in this domain suggested increased responsiveness in high-dose males on PND 29, in response to both the click and tail-pinch stimuli. Although these individual endpoints did not reach statistical significance, the , ethanol is 6.7 kcal/g, and the retention rate of inhaled ethanol is 73% (Martin et al, 2012).…”

“…Further, studies reporting hyperactivity typically use oral ethanol doses of 4 g/kg/d or more during gestation. Oral doses between 3 and 6 g/kg yield peak BECs of 220-280 mg/dL in the dam during gestation (Abel, 1979;Church et al, 1990;Martin et al, 2012). For example, offspring of rats dosed by gavage with 5 g/kg ethanol from GD 8-20, which produced BECs of 270 mg/dL, were~50% more active than controls when tested Fig.…”

“…Our PBPK model (Martin et al, 2012) was used to estimate the total mass of ethanol metabolized (g/day) per day for each ethanol exposure concentration. The amount metabolized per day was multiplied by the energy content of ethanol (6.7 kcal/g), yielding units of kcal/day from ethanol for each inhalation exposure.…”

Prenatal exposure to vapors of gasoline–ethanol blends causes few cognitive deficits in adult rats

“…It is instructive for the purpose of this study to examine these effects in relation to the ethanol content of the vapors (Table 1). Whereas tissue concentrations of the hydrocarbons comprising the gasoline mixtures are not available, blood ethanol concentrations (BECs) from these exposures can be estimated from the concentrations of ethanol in the air via available PBPK models (Martin et al, 2012;Martin et al, 2014). Given that the concentrations of ethanol in the vapor to which the rats were exposed were less than 7000 ppm (Table 1), calculated estimates of peak BEC do not exceed 5 mg/dL for any of the vapors tested .…”

Physiologically based pharmacokinetic modeling of ethyl acetate and ethanol in rodents and humans

“…There are a number of PBPK models previously developed to describe the pharmacokinetics of ethanol in rodents and humans (Dumas-Campagna et al, 2014;Martin et al, 2012;Pastino and Conolly, 2000;Plawecki et al, 2008;Umulis et al, 2005), but currently no models describing ethyl acetate.…”