AbstractPrototype controlled release formulations of ticlopidine hydrochloride were developed, but when administered to humans, these formulations significantly reduced the bioavailability of intact drug in plasma. In order to examine the intestinal permeability characteristics and gastrointestinal metabolism of14C-ticlopidine, we employed anin vitrodiffusion cell system to directly measure the permeation of ticlopidine across various segments of monkey and rabbit intestine. High pressure liquid chromatography was used to determine the amount of intact ticlopidine on both the mucosal and serosal sides of the intestinal tissue.Simulations based upon the known pharmacokinetics of ticlopidine were conducted using STELLA®, a modeling program, to provide insight as to the nature of the decreased bioavailability of these ticlopidine CR dosage forms. These simulations indicate that the absorption of intact ticlopidine is a non-linear phenomena, with inordinately large increases in absorbed intact drug with increases in dose. Conversely, decreases in drug available for immediate absorption, as with the controlled release dosage forms, lead to non-linear decreases in bioavailability. Such a finding is very consistent with the extensive first-pass metabolism suggested from the tissue permeability studies.