Determining the extent of absorption in humans based on mass balance studies using total radioactivity in urine does not take into consideration the extent of degradation of a drug in the GI fluid prior to intestinal membrane permeation. In addition, some methods for determining permeability could be based on loss or clearance of a drug from fluids perfused into the human and/or animal GI tracts either in vivo or in situ. Documenting the fact that drug loss from the GI tract arises from intestinal membrane permeation, rather than a degradation process, will help establish permeability. Stability in the GI tract may be documented using gastric and intestinal fluids obtained from human subjects. Drug solutions in these fluids should be incubated at 37°C for a period that is representative of in vivo drug contact with these fluids; for example, one hour in gastric fluid and three hours in intestinal fluid. Drug concentrations should then be determined using a validated stability-indicating assay method. Significant degradation (> 5%) of a drug in this protocol could suggest potential instability. Obtaining GI fluids from human subjects requires intubation and may be difficult in some cases. Use of GI fluids from suitable animal models and/or simulated fluids such as gastric and intestinal fluids USP can be substituted when properly justified.
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