text: The upper molecular-weight limit for a small molecule is approximately 900 daltons, which allows for the possibility to rapidly diffuse across cell membranes so that it can reach intracellular sites of action. This molecular weight cutoff is also a necessary but insufficient condition for oral bioavailability as it allows for transcellular transport through intestinal epithelial cells.  In addition to intestinal permeability, the molecule must also possess a reasonably rapid rate of dissolution into water and adequate water solubility and moderate to low first pass metabolism. A somewhat lower molecular weight cutoff of 500 daltons (as part of the "rule of five") has been recommended for oral small molecule drug candidates based on the observation that clinical attrition rates are significantly reduced if the molecular weight is kept below this limit.