Direct In Vivo Human Intestinal Permeability (Peff) Determined with Different Clinical Perfusion and Intubation Methods

Abstract

Regional in vivo human intestinal effective permeability (Peff ) is calculated by measuring the disappearance rate of substances during intestinal perfusion. Peff is the most relevant parameter in the prediction of rate and extent of drug absorption from all parts of the intestine. Today, human intestinal perfusions are not performed on a routine basis in drug development. Therefore, it would be beneficial to increase the accuracy of the in vitro and in silico tools used to evaluate the intestinal Peff of novel drugs. This review compiles historical Peff data from 273 individual measurements of 80 substances from 61 studies performed in all parts of the human intestinal tract. These substances include: drugs, monosaccharaides, amino acids, dipeptides, vitamins, steroids, bile acids, ions, fatty acids, and water. The review also discusses the determination and prediction of Peff using in vitro and in silico methods such as quantitative structure-activity relationship, Caco-2, Ussing chamber, animal intestinal perfusion, and physiologically based pharmacokinetic (PBPK) modeling. Finally, we briefly outline how to acquire accurate human intestinal Peff data by deconvolution of plasma concentration-time profiles following regional intestinal bolus dosing.

Translating Human Effective Jejunal Intestinal Permeability to Surface-Dependent Intrinsic Permeability: a Pragmatic Method for a More Mechanistic Prediction of Regional Oral Drug Absorption

“…Under the aforementioned assumption, the regional differences in absorption should be a product of the variable conditions along the GI tract and the variable nature of the intestinal membrane, where the differences in mSA are assumed to play a major role in defining such differences in absorption. This assumes however that the differences in the membrane composition are relatively small across the human intestine, which might not be necessary true as the small-intestinal and colon membrane have different physicochemical properties (62)(63)(64) as well as differences in the mucus layer and UWL composition (65).…”

“…Due to the elevated cost of the clinical investigation of regional human P eff , the use of animal models and in vitro systems such as the Ussing chamber combined with excised human intestinal fragments can provide a reliable alternative for such estimates (3,60,65,66,74,75). In addition, one of the main goals of the Pan-European project Oral Biopharmaceutical Tools (OrBiTo), funded by the Innovative Medicines Initiative (IMI), is to provide the necessary information to improve our understanding of how orally administered drugs become absorbed from the GI tract and to generate better in vitro and in silico tools that allow a better prediction of their in vivo performance (http://www.orbitoproject.eu/objectives).…”

Rate- and Extent-Limiting Factors of Oral Drug Absorption: Theory and Applications

“…We can define the critical permeation number (Pn crit ) as the lowest Pn value that provides the C max and AUC ratios of more than 0.8 against the theoretically highest permeability case of Pn = 20. Pn = 20 is calculated based on the highest permeability value observed in humans ( P eff = 10 × 10 −4 cm/s for glucose) and adjusted for the average molecular weight of modern drugs (400) . Figure shows the relationship between Pn crit and T 1/2 .…”

Application of data mining approach to identify drug subclasses based on solubility and permeability

“…The drug data set used for clustering and classification analysis is presented in Table . It includes a total of 64 model drugs with diverse physicochemical and biopharmaceutical properties: (a) compounds 1–34 were adopted from the data set compiled by Dahlgren et al () for which P eff values have been determined from the intestinal perfusion studies in humans; (b) compounds 35–64 were added based on the extensive physicochemical and biopharmaceutical data reported in the respective FIP Biowaiver Monographs (2004‐2016) (https://www.fip.org/bcs_monographs).…”