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, 17 (5), 1177-92

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

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

Andrés Olivares-Morales et al. AAPS J.

Abstract

Regional intestinal effective permeability (P(eff)) values are key for the understanding of drug absorption along the whole length of the human gastrointestinal (GI) tract. The distal regions of the GI tract (i.e. ileum, ascending-transverse colon) represent the main sites for GI absorption when there is incomplete absorption in the upper GI tract, e.g. for modified release formulations. In this work, a new and pragmatic method for the estimation of (passive) intestinal permeability in the different intestinal regions is being proposed, by translating the observed differences in the available mucosal surface area along the human GI tract into corrections of the historical determined jejunal P(eff) values. These new intestinal P(eff) values or "intrinsic" P(eff)(P(eff,int)) were subsequently employed for the prediction of the ileal absorption clearance (CL(abs,ileum)) for a set of structurally diverse compounds. Additionally, the method was combined with a semi-mechanistic absorption PBPK model for the prediction of the fraction absorbed (f(abs)). The results showed that P(eff,int) can successfully be employed for the prediction of the ileal CL(abs) and the f(abs). P(eff,int) also showed to be a robust predictor of the f(abs) when the colonic absorption was allowed in the PBPK model, reducing the overprediction of f(abs) observed for lowly permeable compounds when using the historical P(eff) values. Due to its simplicity, this approach provides a useful alternative for the bottom-up prediction of GI drug absorption, especially when the distal GI tract plays a crucial role for a drug's GI absorption.

Figures

Fig. 1
Fig. 1
Illustrations of the changes on intestinal mucosal surface area estimated by the different methods. a Changes in the surface area expansion factors (SAEFs) along the length of the small intestine (as a percentage), the SAEF is defined as the ratio between the surface area estimated by a given method and the surface area of a cylinder. b Total mucosal surface area estimated from the different methods (M1 to M3), whereas CSAEF is the total mucosal surface area estimated by applying a constant SAEF of 600-fold along the small intestine. c An illustration of the total surface area estimated for each of the regions of the small intestine and the ascending colon, for the different methods (M1 to M3) and when using the CSAEF. The values were calculated assuming a reference human intestine (see main text for details on the anatomical values employed for the calculations)
Fig. 2
Fig. 2
Upper panel, comparison between jejunal P eff,int calculated by: a M1 (cylindrical SA), b M2 (mSA according to Wilson’s method) and c M3 (mSA according to Helander and Fändriks’ method). Lower panel, prediction of ileal absorption clearance (permeability clearance) employing jejunal P eff and ileal surface area using: d M1, e M2 and f M3. Solid light circles, BCS class 1; solid light squares, BCS class 2; solid dark upper triangles, BCS class 3; and solid dark lower triangles, BCS class 4. Black solid line represents the line of unity, whereas the dashed grey lines represent the twofold error
Fig. 3
Fig. 3
Comparison between different small-intestinal transit models to the describe SITT data. The lines represent the cumulative percentage of the dose reaching the colon for the different SITT models. Red solid line, mSAT model (Weibull transfer between segments); dot- dashed cyan line, full CAT model (seven transit compartments); dashed blue line, CAT model with only three compartments (same first-order transit rate constant for all the segments); dotted green line, CAT model with only three compartments, where the transit was fractionally divided for each segment (based on the segment’s length). The solid dots are the observed cumulative percentage of the dose reaching the colon, as per reference (32)
Fig. 4
Fig. 4
f abs (%) predictions using P eff values from Table II and the mSAT model. Upper panel, no colonic absorption allowed in the mSAT model: a M1 (cylindrical SA), b M2 (mSA according to Wilson’s method), c M3 (mSA according to Helander and Fändriks’ method). Lower panel, colonic absorption allowed in the mSAT model: d M1, e M2 and f M3. Black solid lines represent the line of unity, whereas the dashed grey lines represent the twofold error
Fig. 5
Fig. 5
Simulated P eff * to f abs relationship for the mSAT model. a Colonic absorption not allowed. b Colonic absorption allowed. The lines represent different methods for the estimation of P eff,int. Black solid line, M1; grey long-dashed line, M2; and grey short-dashed line, M3. *For M2 and M3, P eff is re-calculated internally by the mSAT model according to the mSA available in the double-balloon segment. The insert shows the same plots in the semi logarithmic scale
Fig. 6
Fig. 6
Bar chart of the predicted f abs (overall and regional) using the mSAT model and P eff,int for a subset of representatives drugs from Table II (colonic absorption was allowed). Upper panel (a), drugs assumed to be administered in solution; lower panel (b), drugs assumed to be administered as a MR formulation. Each bar represents a different method for the estimation of the absorption (M1, M2 and M3), whereas the shades of grey indicate the proportion of the contribution to the f abs from each intestinal segment

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