A Physiological Model for the Estimation of the Fraction Dose Absorbed in Humans

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Abstract

A physiologically based model for gastrointestinal transit and absorption in humans is presented. The model can be used to study the dependency of the fraction dose absorbed (F(abs)) of both neutral and ionizable compounds on the two main physicochemical input parameters (the intestinal permeability coefficient (P(int)) and the solubility in the intestinal fluids (S(int))) as well as physiological parameters such as the gastric emptying time and the intestinal transit time. For permeability-limited compounds, the model produces the established sigmoidal dependence between F(abs) and P(int). In case of solubility-limited absorption, the model enables calculation of the critical mass-solubility ratio, which defines the onset of nonlinearity in the response of fraction absorbed to dose. In addition, an analytical equation to calculate the intestinal permeability coefficient based on the compound's membrane affinity and molecular weight was used successfully in combination with the physiologically based pharmacokinetic (PB-PK) model to predict the human fraction dose absorbed of compounds with permeability-limited absorption. Cross-validation demonstrated a root-mean-square prediction error of 7% for passively absorbed compounds.

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