Species Extrapolation of Life-Stage Physiologically-Based Pharmacokinetic (PBPK) Models to Investigate the Developmental Toxicology of Ethanol Using In vitro to In vivo (IVIVE) Methods

Abstract

To provide useful alternatives to in vivo animal studies, in vitro assays for dose-response assessments of xenobiotic chemicals must use concentrations in media and target tissues that are within biologically-plausible limits. Determining these concentrations is a complex matter, which can be facilitated by applying physiologically-based pharmacokinetic (PBPK) models in an in vitro to in vivo extrapolation (IVIVE) paradigm. We used ethanol (EtOH), a ubiquitous chemical with defined metrics for in vivo and in vitro embryotoxicity, as a model chemical to evaluate this paradigm. A published series of life-stage PBPK models for rats was extended to mice, yielding simulations that adequately predicted in vivo blood EtOH concentrations (BECs) from oral, intraperitoneal, and intravenous routes in nonpregnant and pregnant adult mice. The models were then extrapolated to nonpregnant and pregnant humans, replicating BEC data within a factor of two. The rodent models were then used to conduct IVIVEs for rodent and whole-embryo culture embryotoxicity data (neural tube closure defects, morphological changes). A second IVIVE was conducted for exposure scenarios in pregnant women during critical windows of susceptibility for developmental toxicity, such as the first 6-to-8 weeks (prerecognition period) or mid-to-late pregnancy period, when EtOH consumption is associated with fetal alcohol spectrum disorders. Incorporation of data from human embryonic stem cell studies led to a model-supported linkage of in vitro concentrations with plausible exposure ranges for pregnant women. This effort demonstrates benefits and challenges associated with use of multispecies PBPK models to estimate in vivo tissue concentrations associated with in vitro embryotoxicity studies.

Developmental Ethanol Exposure Leads to Long-Term Deficits in Attention and Its Underlying Prefrontal Circuitry

“…These BEC values are similar to those found in previous studies following binge-pattern oral administration of ethanol to developing mice (Jiang et al, 2007; Cui et al, 2010; Kane et al, 2011), rats (Maier et al, 1996; Ryan et al, 2008; Brocardo et al, 2012) and guinea pigs (Bailey et al, 2001; Iqbal et al, 2006; Olmstead et al, 2009), where neurocognitive and neurological teratogenic effects were observed. It should be noted that these BEC values are also similar to those predicted in a recent ethanol pharmacokinetic modeling study for pregnant mice after a single 4-g/kg oral dose of ethanol (Martin et al, 2015). However, the same study found these values to be approximately one-half of those predicted for pregnant humans after the same ethanol dose (Martin et al, 2015).…”

“…It should be noted that these BEC values are also similar to those predicted in a recent ethanol pharmacokinetic modeling study for pregnant mice after a single 4-g/kg oral dose of ethanol (Martin et al, 2015). However, the same study found these values to be approximately one-half of those predicted for pregnant humans after the same ethanol dose (Martin et al, 2015). There was no effect of ethanol treatment on the amount of food consumed by dams or litters, although there was a small decrease in the amount of food consumed by dams of both groups on the first day of treatment only (data not shown).…”

A Computational Framework for Interspecies Pharmacokinetics, Exposure and Toxicity Assessment of Gold Nanoparticles

“…Calculated using interspecies and in vitro to in vivo extrapolation methods [45] Optimal human model [39] derived from the low-dose rat model Unsuccessful extrapolation…”

Physiology of the Neonatal Gastrointestinal System Relevant to the Disposition of Orally Administered Medications

“…This apparent decrease in oral uptake rate constant with age may simply reflect changes in the metabolic capacity of the GIT. In contrast, for ethanol, a nonlipophilic chemical with high water solubility, the apparent fitted oral uptake constant values remained the same until near weaning, at which time they increased slightly (Martin et al, 2015). This increase in first-order uptake rate constants near birth may be related to increases in paracellular transport in the intestinal epithelium.…”