Purpose: A recent bioavailability study raises questions about the universality of the permeability enhancing effect of chitosan on poorly permeable drugs1. Unexpectedly, chitosan reduced the bioavailability of acyclovir. The objective of this study was to establish a hypothesis that could be tested using a mechanistic oral absorption model to help establish a possible mechanism for this result.
Methods: Experiments were conducted in vitro to measure permeability through rat intestinal tissue and changes in pig mucus viscosity and rheology in the presence of chitosan. Effective permeability (Peff) values were incorporated into a PBPK model, and the aqueous diffusion coefficient (D) of acyclovir was varied according to viscosity observations. Amechanistic PBPK model for acyclovir was developed using GastroPlus™ 9.6 (Simulations Plus, Inc.) Advanced Compartmental Absorption and Transit™ (ACAT™) model and PBPKPlus™ module to mechanistically explain absorption, distribution, and clearance mechanisms. The kinetic parameters (Km and Vmax) for alcohol dehydrogenase (ADH1) mediated metabolism were obtained from literature (Km) or fitted (Vmax) to intravenous (IV) and oral (PO) formulations. The model utilized an all tissue permeability-limited model with active renal secretion mediated by two transporters: 1) organic anion transporter 2 (OAT2) on the basolateral membrane and 2) multidrug and toxin 1 (MATE1) on the apical membrane. The model was developed using IV and PO data from oral administration in the absence of chitosan. The model was further validated by comparing simulated and observed plasma concentration-time profiles for acyclovir obtained from clinical studies in the presence of two concentrations of chitosan.
Chitosan decreased acyclovir permeability and increased mucus viscosity. Mucin showed concentration dependent viscosity within the experimental shear rate range. Viscosity was mostly undetected at 15 mg/mL, but it ranged from 2 to 5 mPas and from 7 to 10 mPas, at 30 and 45 mg/mL, respectively. In addition, chitosan addition changed the system rheology from Newtonian to a pseudoplastic behavior. The results from a mechanistic oral absorption modeling support a hypothesis that a chitosan-mucus interaction might be responsible for a reduction in acyclovir paracellular permeability by decreasing the effective diffusion coefficient of acyclovir in vivo. The model accurately predicted acyclovir’s bioavailability and the chitosan effect by considering both Peff and D (see Figure 1).
Figure 1. Observed and predicted plasma concentration vs time profile after oral administration of acyclovir 200 mg. Observed plasma concentration profiles were extracted from Kubbinga et al. at 0 (triangles), 1.6 g/L (circles) and 4.0 (squares) g/L of chitosan1. Predicted profiles are shown as simulation outputs at 0 (green line), 1.6 g/L (orange line) and 4.0 g/L (blue line) of chitosan
The absorption and pharmacokinetics of acyclovir in healthy subjects were modeled using in vitro and in silico data describing the drug’s physicochemical and biopharmaceutical properties, along with in vitro and fitted enzymatic kinetics ADH1, OAT2, and MATE1. The model was successfully applied to capture the gut and liver metabolism of acyclovir by ADH1, and renal elimination mediated by secretory influx and efflux transporters. The application of a mechanistic oral absorption/PBPK model helped to identify the critical parameters that can explain the anomalous decrease in AUC induced by chitosan which is normally considered to be an excipient that enhances the absorption of poorly permeable drugs.
Micheal Bolger– Chief Scientist, Simulations Plus, Inc., Lancaster, California
Mauricio Garcia– Químico Farmacéutico" (Pharmacy certificate) in a 5-years programm,, "Pontificia Universidad Católica de Chile, Mainz, Rheinland-Pfalz
Peter Langguth– Professor, Johannes Gutenberg University Mainz, Mainz, Rheinland-Pfalz
Michael Bolger– Chief Scientist, Simulations Plus, Inc.