![]() The solubility-permeability interplay and oral drug formulation design: Two heads are better than one. Prediction of solubility and permeability class membership: Provisional BCS classification of the world’s top oral drugs. A theoretical basis for a biopharmaceutic drug classification: The correlation of in vitro drug product dissolution and in vivo bioavailability. The potential link between segmental-dependent intestinal permeability and adequate oral absorption of BCS Class IV drugs may aid to develop challenging drugs as successful oral products.īCS class IV drugs biopharmaceutics furosemide intestinal absorption oral drug delivery physiologically-based pharmacokinetic (PBPK) modeling segmental-dependent intestinal permeability.Īmidon G.L., Lennernäs H., Shah V.P., Crison J.R. Nevertheless, this absorption window so early on in the SI rules out the suitability of controlled-release furosemide formulations, as confirmed by the in-silico results. The data reveals the absorption window of furosemide in the proximal SI, allowing adequate absorption and consequent effect, despite its class IV characteristics. Computational simulations clearly showed the effect of furosemide's regional-dependent permeability on its absorption, as well as the critical role of the drug's absorption window on the overall bioavailability. Theoretical physicochemical analysis based on ionization, pK a, and partitioning predicted the same trend and confirmed the experimental results. The opposite trend was evident for metoprolol. Similarly, segmental-dependent in-vivo intestinal permeability was revealed as the intestinal region becomes progressively distal, and the pH gradually increases, the permeability of furosemide significantly decreased. ![]() Log D of furosemide at the three pH values 6.5, 7.0, and 7.5 (representing the conditions throughout the SI) showed a downward trend. Furosemide was found to be a low-solubility compound. Metoprolol was used as the low/high permeability class boundary. In addition, advanced in-silico simulations (GastroPlus ®) were used to elucidate furosemide regional-dependent absorption pattern. Furosemide solubility, physicochemical properties, and intestinal permeability were thoroughly investigated in-vitro and in-vivo throughout the SI. ![]() In this work, we investigated the solubility/permeability of BCS class IV drug, furosemide, considering the complexity of the entire small intestine (SI). ![]() While solubility is often predictable, intestinal permeability is rather complicated and highly dependent on many biochemical/physiological parameters. Biopharmaceutical classification system (BCS) class IV drugs (low-solubility low-permeability) are generally poor drug candidates, yet, ~5% of oral drugs on the market belong to this class. ![]()
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