Development of a Novel Simplified PBPK Absorption Model to Explain the Higher Relative Bioavailability of the OROS® Formulation of Oxybutynin

Tissue-to-plasma water partition coefficients (Kpu's) form an integral part of whole body physiologically based pharmacokinetic (WBPBPK) models. This research aims to improve the predictability of Kpu values for moderate-to-strong bases (pK(a) > or = 7), by developing a mechanistic equation that accommodates the unique electrostatic interactions of such drugs with tissue acidic phospholipids, where the affinity of this interaction is readily estimated from drug blood cell binding data. Additional model constituents are drug partitioning into neutral lipids and neutral phospholipids, and drug dissolution in tissue water. Major assumptions of this equation are that electrostatic interactions predominate, drugs distribute passively, and non-saturating conditions prevail. Resultant Kpu predictions for 28 moderate-to-strong bases were significantly more accurate than published equations with 89%, compared to 45%, of the predictions being within a factor of three of experimental values in rat adipose, bone, gut, heart, kidney, liver, muscle, pancreas, skin, spleen and thymus. Predictions in rat brain and lung were less accurate probably due to the involvement of additional processes not incorporated within the equation. This overall improvement in prediction should facilitate the further application of WBPBPK modeling, where time, cost and labor requirements associated with experimentally determining Kpu's have, to a large extent, deterred its application. (c) 2005 Wiley-Liss, Inc. and

The gastrointestinal transit of pharmaceutical dosage forms has been measured in 201 studies in normal subjects using gamma scintigraphy. Solutions, small pellets, and single units (matrix tablets and osmotic pumps) were administered with different amounts of food in the stomach, ranging from fasted state to heavy breakfast. Gastric emptying was affected by the nature of the dosage form and the presence of food in the stomach. Solutions and pellets were emptied even when the stomach was in the digestive mode, while single units were retained for long periods of time, depending on the size of the meal. In contrast, measured intestinal transit times were independent of the dosage form and fed state. The small intestinal transit time of about three hours (mean +/- 1 h SEM) has implications for the design of dosage forms for the sustained release of drugs in specific positions in the gastrointestinal tract.