, 1998 and Vertzoni et al., 2005). Capmatinib research buy Ethanol can act as a cosolvent and increase the Sapp in gastrointestinal fluids. This may therefore affect the absorption of poorly soluble drugs. Common modified release formulations carrying high doses of drugs have been shown to disintegrate prematurely and unload the complete dose in the small intestine

in response to ethanol intake ( Fadda et al., 2008 and Walden et al., 2007). This phenomenon is referred to as dose dumping and can lead to increased and potentially hazardous plasma concentrations and adverse side effects of drugs with narrow therapeutic window ( Lennernäs, 2009). A well-known example of this phenomenon is hydromorphone for which one formulation was withdrawn from the market in 2005 after reports of ethanol-induced, dose-dumping-related, adverse drug reactions (ADR). The withdrawn product was a capsule with an extended release formulation consisting of hotmelt extruded granules of the drug, ammonio methacrylate copolymer type b and ethylcellulose. The latter GSK1349572 has been shown to be

sensitive to ethanol in dissolution tests ( Fadda et al., 2008). Following this observation the FDA composed a number of substance specific guidelines (e.g., bupropion hydrochloride, morphine sulfate and trospium chloride) to test for ethanol sensitivity of modified release formulations. In these guidelines dissolution behavior should be assessed for 2 h with 0%, 5%, 20% and 40% v/v ethanol in an acidic medium reflecting the gastric milieu ( Anand et al., 2011). We hypothesized that immediate release formulations of drugs with low solubility in gastrointestinal fluids may, in a similar fashion as extended release formulations during dose-dumping,

show increased absorption in response to alcohol intake. This hypothesis is based on the large drug load of such compounds which is not dissolved during gastrointestinal transit under normal fasted conditions. If the presence of ethanol in gastrointestinal fluids increases the dissolution rate and/or the Sapp of a compound, it may also affect the absorption Linifanib (ABT-869) profile of that drug ( Fig. 1). Indeed, in a previous study investigating 22 compounds in FaSSIF, we found that non-ionizable compounds and weak acids in particular were at a high risk for obtaining significantly different dissolution profiles when administered with ethanol. However, ethanol is rapidly absorbed in the intestinal tract and the impact on absorption was not revealed in the previous study. For instance, it has been shown that if ethanol is co-administered with water, the ethanol disappears from the gastric compartment within 30 min and half of the dose is emptied into the duodenum within 5 min ( Levitt et al., 1997).