Drug absorption from drug products may be affected by pharmaceutical excipients and/or food additives through different mechanisms. Chitosan is a recognized nutraceutical, with potential as an excipient due to its permeability enhancer properties. While chitosan properties have been evaluated in in vitro and pre-clinical models, studies in humans are scarce. Unexpectedly, a controlled clinical trial showed chitosan actually reduced acyclovir bioavailability. The effect seems to be related to an interaction with gastrointestinal mucus that prevents further absorption, although more in depth research is needed to unravel the mechanism. In this paper, we propose a mechanism underlying this excipient effect. The mucus - chitosan interaction was characterized and its effect on acyclovir diffusion, permeation and bioaccessibility was investigated. Further, pharmacokinetic modeling was used to assess the clinical relevance of our findings. Results suggest that in situ coacervation between endogenous mucus and chitosan rapidly entrap 20-30% of acyclovir dissolved dose in the intestinal lumen. This local reduction of acyclovir concentration together with its short absorption window in the small intestine would explain the reduction in acyclovir Cmax and AUC. This study highlights the importance of considering mucus in any biorelevant absorption model attempting to anticipate the effect of chitosan on drug absorption.
Keywords: Bioavailability; Drug absorption; Drug food interaction; Drug neutraceutical interaction; Mucus encapsulation; Pharmacokinetics; Systemic availability.
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