A Modified Physiological BCS for Prediction of Intestinal Absorption in Drug Discovery

• Published in: Molecular pharmaceutics 2010-10, Vol.7 (5), p.1478-1487
• Main Authors: Zaki, Noha M, Artursson, Per, Bergström, Christel A. S
• Format: Article
• Language: English
• Subjects: Administration, Oral; BCS; Biopharmaceutics; biorelevant dissolution medium; Cell Line; Chemistry, Pharmaceutical; Drug Discovery; FARMACI; fasted state; Fasting - metabolism; fed state; Humans; Hydrogen-Ion Concentration; Intestinal Absorption; intestinal fluid; Models, Biological; Permeability; Pharmacokinetics; PHARMACY; Solubility
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/mp100124f

In this study, the influence of physiologically relevant media on the compound position in a biopharmaceutical classification system (BCS) which resembled the intestinal absorption was investigated. Both solubility and permeability limited compounds (n = 22) were included to analyze the importance of each of these on the final absorption. Solubility was determined in three different dissolution media, phosphate buffer pH 6.5 (PhB 6.5), fasted state simulated intestinal fluid (FaSSIF), and fed state simulated intestinal fluid (FeSSIF) at 37 °C, and permeability values were determined using the 2/4/A1 cell line. The solubility data and membrane permeability values were used for sorting the compounds into a BCS modified to reflect the fasted and fed state. Three of the seven compounds sorted as BCS II in PhB 6.5 (high permeability, low solubility) changed their position to BCS I when dissolved in FaSSIF and/or FeSSIF (high permeability, high solubility). These were low dosed (20 mg or less) lipophilic molecules displaying solvation limited solubility. In contrast, compounds having solid-state limited solubility had a minor increase in solubility when dissolved in FaSSIF and/or FeSSIF. Although further studies are needed to enable general cutoff values, our study indicates that low dosed BCS Class II compounds which have solubility normally restricted by poor solvation may behave as BCS Class I compounds in vivo. The large series of compounds investigated herein reveals the importance of investigating solubility and dissolution under physiologically relevant conditions in all stages of the drug discovery process to push suitable compounds forward, to select proper formulations, and to reduce the risk of food effects.