Impact of sex, strain, and age on blood ethanol concentration and behavioral signs of intoxication during ethanol vapor exposure.

Animal models of alcohol drinking and dependence are a critical resource for understanding the neurobiological mechanisms and development of more effective treatments for alcohol use disorder (AUD). Because most rat strains do not voluntarily consume large enough quantities of alcohol to adequately model heavy drinking, dependence, and withdrawal-related symptoms, researchers frequently turn to experimenter administered methods to investigate how prolonged and repeated exposure to large quantities of alcohol impacts brain and behavior. Vaporized ethanol is a common method used for chronically subjecting rodents to alcohol and has been widely used to model both binge and dependence-inducing heavy drinking patterns observed in humans. Rodent strain, sex, and age during exposure are all well-known to influence outcomes in experiments utilizing intraperitoneal or intragastric methods of repeated ethanol exposure. Yet, despite its frequent use, the impact of these variables on outcomes associated with ethanol vapor exposure has not been widely investigated. The present study analyzed data generated from over 700 rats across an eight-year period to provide a population-level assessment of variables influencing level of intoxication using vapor exposure. Our findings reveal important differences with respect to strain, sex, and age during ethanol exposure in the relationship between blood ethanol concentration and behavioral signs of intoxication. These data provide valuable scientific and practical insight for laboratories utilizing ethanol vapor exposure paradigms to model AUD in rats.

Importance of in vitro dissolution conditions for the in vivo predictability of an amorphous solid dispersion containing a pH-sensitive carrier.

The present study investigated the influence of in vitro dissolution conditions on the in vivo predictability of an amorphous solid dispersion of celecoxib (CCX) in the pH-sensitive polymer Eudragit® S 100. Different doses of a 25:75w/w% CCX:Eudragit® S 100 amorphous solid dispersion (CCX:EUD) were investigated. During in vitro dissolution a significant effect of the pH of the dissolution media on the release of CCX was observed. In fasted state simulated intestinal fluid (FaSSIF) pH 6.5, the release of CCX from the amorphous solid dispersion was comparable to that of crystalline CCX and lower than that of amorphous CCX whereas in FaSSIF pH 7.4, the release was significantly increased compared to both crystalline and amorphous CCX. With a 3-fold increase in the exposure of CCX:EUD compared to crystaline CCX. The in vivo data also suggested that Eudragit® S 100 was suitable as a carrier in amorphous solid dispersions of CCX. In vitro-in vivo correlation demonstrated that the in vitro data obtained in FaSSIF pH 7.4 was more predictive for the in vivo performance than that obtained in FaSSIF pH 6.5. Consequently, the findings of this study underline that when predicting the in vivo performance of amorphous solid dispersions with pH-sensitive polymers, it is imperative that the in vitro dissolution conditions are carefully considered.

Effect of polymer type and drug dose on the in vitro and in vivo behavior of amorphous solid dispersions.

This study investigated the non-sink in vitro dissolution behavior and in vivo performance in rats of celecoxib (CCX) amorphous solid dispersions with polyvinyl acetate (PVA), polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose (HPMC) at different drug doses. Both in vitro and in vivo, the amorphous solid dispersions with the hydrophilic polymers PVP and HPMC led to higher areas under both, the in vitro dissolution and the plasma concentration-time curves (AUC) compared to crystalline and amorphous CCX for all doses. In contrast, the amorphous solid dispersion with the hydrophobic polymer PVA showed a lower AUC both in vitro and in vivo than crystalline CCX. For crystalline CCX and CCX:PVA, the in vitro AUC was limited by the low solubility of the drug and the slow release of the drug from the hydrophobic polymer, respectively. For the supersaturating formulations, amorphous CCX, CCX:PVP and CCX:HPMC, the in vitro performance was mainly dependent on the dissolution rate and precipitation/crystallization inhibition of the polymer. As expected, the crystallization tendency increased with increasing dose, and therefore the in vitro AUCs did not increase proportionally with dose. Even though the in vivo AUC for all formulations increased with increasing dose, the relative bioavailability decreased significantly, indicating that the supersaturating formulations also crystallized in vivo and that the absorption of CCX was solubility-limited. These findings underline the importance of evaluating relevant in vitro doses, in order to rationally assess the performance of amorphous solid dispersions and avoid confusion in early in vivo studies.