Fasted and fed state human duodenal fluids: Characterization, drug solubility, and comparison to simulated fluids and with human bioavailability

D Dahlgren,M Venczel,J.-P Ridoux,C Skjöld,A Müllertz,R Holm,P Augustijns,P.M Hellström,H Lennernäs

doi:10.1016/j.ejpb.2021.04.005

Abstract

Accurate in vivo predictions of intestinal absorption of low solubility drugs require knowing their solubility in physiologically relevant dissolution media. Aspirated human intestinal fluids (HIF) are the gold standard, followed by simulated intestinal HIF in the fasted and fed state (FaSSIF/FeSSIF). However, current HIF characterization data vary, and there is also some controversy regarding the accuracy of FaSSIF and FeSSIF for predicting drug solubility in HIF. This study aimed at characterizing fasted and fed state duodenal HIF from 16 human volunteers with respect to pH, buffer capacity, osmolarity, surface tension, as well as protein, phospholipid, and bile salt content. The fasted and fed state HIF samples were further used to investigate the equilibrium solubility of 17 representative low-solubility small-molecule drugs, six of which were confidential industry compounds and 11 were known and characterized regarding chemical diversity. These solubility values were then compared to reported solubility values in fasted and fed state HIF, FaSSIF and FeSSIF, as well as with their human bioavailability for both states. The HIF compositions corresponded well to previously reported values and current FaSSIF and FeSSIF compositions. The drug solubility values in HIF (both fasted and fed states) were also well in line with reported solubility data for HIF, as well as simulated FaSSIF and FeSSIF. This indicates that the in vivo conditions in the proximal small intestine are well represented by simulated intestinal fluids in both composition and drug equilibrium solubility. However, increased drug solubility in the fed vs. fasted states in HIF did not correlate with the human bioavailability changes of the same drugs following oral administration in either state.

Highlights

A systemically acting drug administered orally must be absorbed from the gastrointestinal (GI) tract and avoid first-pass extraction in the gut wall and liver before it can exert its pharmacological effect
Molecular diversity of the drug data set Principal component analysis of the reference dataset with 674 compounds and 12 physicochemical descriptors resulted in two prin cipal components
The score- and loading plots are presented in Fig. 1a and b, respectively, where visual analysis of the loading plot suggests that the general property directions in the plots are molecular size in principal component 1 (x-axis) and hydrophobicity in principal component 2

Summary

Introduction

A systemically acting drug administered orally must be absorbed from the gastrointestinal (GI) tract and avoid first-pass extraction in the gut wall and liver before it can exert its pharmacological effect. The fraction absorbed from the intestine is determined by the velocity (length/time) of drug transport across the apical intestinal cell mem brane, i.e. the permeability. It is determined by the drug dissolution rate and solubility in the intestinal lumen, because only aqueous dis solved drug molecules cross the intestinal epithelial barrier. Solubility is the more frequently observed limitation, because candidate drugs in drug discovery and early development tend to have limited aqueous solubility and slow dissolution rate in the GI lumen [1]

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