Ethanol Predominantly Constricts Pre-sinusoids of Isolated Perfused Livers of Rat, Guinea pig and Mouse

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.

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Maternal separation on the ethanol-preferring adult rat liver structure

Rosa-Toledo

Almeida-Chuffa

Martinez

et al. 2015

Annals of Hepatology

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Ethanol Predominantly Constricts Pre-sinusoids of Isolated Perfused Livers of Rat, Guinea pig and Mouse

Abstract: Ethanol predominantly constricts pre-sinusoids in rat, guinea pig and mouse livers, although the mouse liver response was much weaker. Ethanol-induced pre-sinusoidal constriction is accompanied by reduction of liver blood volume in guinea pigs and rats.

Cited by 3 publications

References 23 publications

Albumin-based nanoparticles as contrast medium for MRI: vascular imaging, tissue and cell interactions, and pharmacokinetics of second-generation nanoparticles

Albumin-based nanoparticles as contrast medium for MRI: vascular imaging, tissue and cell interactions, and pharmacokinetics of second-generation nanoparticles

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

Maternal separation on the ethanol-preferring adult rat liver structure

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