ABSTRACT
A gastric-retentive formulation amenable to dosing in rodents has the potential to enable sustained release in a preclinical setting. This may be useful to provide systemic exposure over a longer duration or to increase duration of exposure for compounds with targets localized in the gastrointestinal tract. Previous work has shown that a mixture of 1% sodium alginate and 0.625% karaya gum in the presence of a calcium chelator can form gels in situ that are gastric retained in rats. The aim of this work was to define the physicochemical boundaries of compounds within this technology and their relation to in vivo release using a series of model compounds with high permeability but varying solubility. In vitro data demonstrated a good correlation between solubility and initial release rates from the gels. In vivo studies were conducted in Sprague-Dawley rats to compare the exposure profile of compounds dosed in gel relative to a standard formulation. In vivo data were consistent with trends from the in vitro studies. These data suggest that, in conjunction with an understanding of compound solubility, sodium alginate/karaya gum gels may be a useful tool to modulate exposure profiles in rodent models in a preclinical setting.
Subject(s)
Alginates/chemistry , Antihypertensive Agents/pharmacokinetics , Cyclooxygenase Inhibitors/pharmacokinetics , Delayed-Action Preparations/chemistry , Ibuprofen/pharmacokinetics , Metoprolol/pharmacokinetics , Pyrazoles/pharmacokinetics , Sulfonamides/pharmacokinetics , Administration, Oral , Animals , Antihypertensive Agents/administration & dosage , Antihypertensive Agents/chemistry , Celecoxib , Cyclooxygenase Inhibitors/administration & dosage , Cyclooxygenase Inhibitors/chemistry , Gastric Mucosa/metabolism , Gels/chemistry , Glucuronic Acid/chemistry , Hexuronic Acids/chemistry , Ibuprofen/administration & dosage , Ibuprofen/chemistry , Male , Metoprolol/administration & dosage , Metoprolol/chemistry , Permeability , Pyrazoles/administration & dosage , Pyrazoles/chemistry , Rats , Rats, Sprague-Dawley , Solubility , Sulfonamides/administration & dosage , Sulfonamides/chemistryABSTRACT
A variety of emerging chemicals of concern are released continuously to surface water through the municipal wastewater effluent discharges. The ability to rapidly determine bioaccumulation of these contaminants in exposed fish without sacrificing the animal (i.e. in vivo) would be of significant advantage to facilitate research, assessment and monitoring of their risk to the environment. In this study, an in vivo solid phase micro-extraction (SPME) approach was developed and applied to the measurement of a variety of emerging contaminants (carbamazepine, naproxen, diclofenac, gemfibrozil, bisphenol A, fluoxetine, ibuprofen and atrazine) in fish. Our results indicated in vivo SPME was a potential alternative extraction technique for quantitative determination of contaminants in lab exposures and as well after exposure to two municipal wastewater effluents (MWWE), with a major advantage over conventional techniques due to its ability to non-lethally sample tissues of living organisms.
