Determinants of Intestinal Availability for P-glycoprotein Substrate Drugs Estimated by Extensive Simulation With Mathematical Absorption Models

Abstract

In this study, intestinal drug-drug interactions (DDIs) for substrate drugs of P-glycoprotein were simulated extensively using the extended Q model and translocation model to explore the determinants of DDI. The results of analyses using both models suggested that permeability and active efflux clearance were the major factors that influenced the fraction absorbed (F). The results of simulation for 100 virtual drugs in which parameters were generated considering the actual values of commercially available drugs suggested that the ratio of the pH-corrected passive permeability to the intrinsic efflux clearance (P/CL) relative to that of digoxin would be a useful and quantitative index of P-glycoprotein (P-gp)-mediated DDI risk at lower doses. At higher doses, such as 100 mg, the risk of P-gp-mediated DDI would be significantly reduced because of saturation of P-gp efflux. The simulation suggested that although drugs with lower permeability were more susceptible, even drugs with higher permeability than metoprolol, a representative highly permeable drug, such as BCS class 1 and 2, may experience DDIs owing to P-gp inhibition. Overall, this study demonstrated the usefulness of mathematical intestinal models when only limited observational data are available.

Significance of Basal Membrane Permeability of Epithelial Cells in Predicting Intestinal Drug Absorption

“…In the present study, including the A-to-B and B-to-A permeation and preload efflux experiments, linear kinetics were assumed with the exception of quinidine to avoid excessive complexity. It is noteworthy that this study evaluated the K m of quinidine while taking into account the contribution of intracellular binding and the permeability of the B-side, thus resulting in a significantly lower value than that previously reported (Takano et al, 2016), and this was used to predict in vivo dose dependency that resulted in a clear improvement in accuracy, particularly at the lower dose range where prediction accuracy has been reported to be poor (Ando et al, 2017). The unexpected profile of A to B permeability of fexofenadine in the quinidine combination experiment might be due to inhibition by quinidine of an unidentified uptake transporter on the A membrane.…”

Comparative in silico prediction of P‐glycoprotein‐mediated transport for 2010–2020 US FDA‐approved drugs using six Web‐tools

“…The cause for such a discrepancy is rather unclear. It may reflect the fact that drugs classified as P‐gp non‐substrates according to FDA criteria may be in fact poor substrates, as discussed above, or that their P‐gp‐mediated transport may be masked by saturation of the pump in in vitro assays, due to the use of high drug concentrations, as already demonstrated for saturation of intestinal P‐gp by high intraluminal drug concentrations (Ando et al., 2017). It may also be due to the presence of various substrate binding sites on P‐gp (Shapiro & Ling, 1997), which is usually unfortunately not documented by predictive tools.…”