The Influence of Fed State Lipolysis Inhibition on the Intraluminal Behaviour and Absorption of Fenofibrate from a Lipid-Based Formulation

Marlies Braeckmans,Joachim Brouwers,Cécile Servais,Patrick Augustijns,Jan Tack,Danny Riethorst

doi:10.3390/pharmaceutics14010119

Abstract

The bioavailability of lipophilic drugs may or may not be increased when administered with food due to increased solubilisation in fed state gastrointestinal (GI) fluids. The in vivo interplay between drug solubilisation, lipid phase digestion and drug absorption is complex and remains poorly understood. This study aimed to investigate the role of fed state GI lipolysis on the intraluminal behaviour and absorption of fenofibrate, formulated as the lipid-based formulation Fenogal. Therefore, a crossover study was performed in healthy volunteers using orlistat as lipase inhibitor. Fenofibrate concentrations were determined in the proximal jejunum and linked to simultaneously assessed systemic fenofibric acid concentrations. Inhibition of lipolysis by orlistat resulted in a faster onset of absorption in 4 out of 6 volunteers, reflected by a decrease in systemic Tmax between 20 and 140 min. In addition, the increase of undigested lipids present in the small intestine upon orlistat co-administration sustained drug solubilisation for a longer period, resulting in higher fenofibrate concentrations in the jejunum and improved absorption in 5 out of 6 volunteers (median AUC0–8h 8377 vs. 5832 μM.min). Sustaining drug solubilisation in the lipid phase may thus contribute to the absorption of lipophilic drugs. More research into the different mechanisms underlying lipophilic drug absorption from fed state media at different levels of digestion is warranted.

Highlights

To this day, it remains a challenge to develop novel formulations enhancing the oral bioavailability of lipophilic drugs
A crossover study in 6 volunteers was performed to evaluate the effect of fed state lipolysis inhibition on fenofibrate absorption after oral administration of the lipid-based formulations (LBFs) Fenogal
In the presence of orlistat, a lipid layer could be observed on top of multiple centrifuged fluids from the different volunteers. Such a lipid layer was absent in the jejunal fluids aspirated in the fed state without orlistat, indicating a fast and more complete lipolysis of the liquid meal in the stomach and proximal part of the small intestine

Summary

Introduction

It remains a challenge to develop novel formulations enhancing the oral bioavailability of lipophilic drugs Often, these drugs display a large intra- and interindividual variability due to their poor solubility in the aqueous luminal environment of the gastrointestinal (GI) tract, which is influenced by the presence of solubilising structures, such as (mixed-)micelles, vesicles and lipid droplets. These drugs display a large intra- and interindividual variability due to their poor solubility in the aqueous luminal environment of the gastrointestinal (GI) tract, which is influenced by the presence of solubilising structures, such as (mixed-)micelles, vesicles and lipid droplets In this respect, a variable food effect can often be observed depending on the prandial state at the time of drug intake and the characteristics of the meal [1,2]. Triacylglycerols (TAGs) break down into diacylglycerols (DAGs), monoacylglycerols (MAGs) and free fatty acids (FFAs), which in turn are incorporated in different types of colloidal structures with the aid of bile salts.

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