The nested enzyme-within-enterocyte (NEWE) turnover model for predicting dynamic drug and disease effects on the gut wall

Abstract

The nested enzyme-within-enterocyte (NEWE) turnover model for predicting dynamic drug and disease effects on the gut wall.

Quantitative Proteomics of Clinically Relevant Drug-Metabolizing Enzymes and Drug Transporters and Their Intercorrelations in the Human Small Intestine

“…Drug absorption across the gut wall is a complex process. Drug bioavailability depends on the physicochemical properties of the drug and formulation and the activity of DMEs and drug transporters in the intestine (Olivares-Morales et al, 2015;Gao et al, 2017;Cristofoletti et al, 2018;Darwich et al, 2019). Regional differences in relative expression of enzymes and transporters can therefore play a significant role in defining the amount of drug that enters systemic circulation unchanged Drozdzik et al, 2014).…”

Application of the Nested Enzyme‐Within‐Enterocyte (NEWE) Turnover Model for Predicting the Time Course of Pharmacodynamic Effects

“…A previous iteration of the PK module in the NEWE-PD model was validated in our previous study, where the NEWE model appeared to outperform the conventional approach for predicting disease effects on oral absorption. 25 On the other hand, the validation of the PD module, which was added in this study, was difficult due to the lack of enterocyte-targeting drugs to which the NEWE-PD model is applicable. This limitation should be addressed by re-evaluating the PD module for enterocyte-targeting drugs with the following features developed in the future.…”

“…Because such a hypothetical question is an area where MIDD exerts its true potential, 23,24 we explored the potential impact of enterocyte turnover on the PDs by extending the existing enterocyte turnover model for PDs. 25 The NEWE-PD model was developed by adding the following features to the original model 25 : (1) PD motif; the one-step binding model was used to express drug-target binding, and target occupancy was used as an index of PDs. In addition to target turnover, degradation of drug-target complex was assumed as per the target-mediated drug disposition model.…”

“…The NEWE model for PDs (NEWE-PD) is based on the original NEWE model structure (Figure 1a). 25 The model consists of an oral dose depot, intestinal lumen, enterocytes, lamina propria, liver, and central compartments. The description of the gut wall is presented below, and the details of other compartments and parameter values are given in the Supplementary Material, Section 1.…”

“…23,24 Previously, we have shown that the nested-enzyme-within-enterocyte (NEWE) turnover model, which incorporates nested enterocyte and metabolic enzyme turnover, can accurately describe the change in PKs in special populations with altered enterocyte kinetics. 25 Here, we aimed to explore the impact of enterocyte turnover on PDs of enterocyte-targeting drugs by extending the NEWE model to account for PDs. Changes in PDs derived from the IIV in enterocyte lifespan were also investigated through simulations over realistic parameter ranges obtained through a comprehensive literature search.…”