(T1330-04-23) Concurrent Effect of Lipids and Surfactants on Intestinal Drug Absorption: A Modeling Approach

Purpose: Surfactants enhance the solubilization and absorption of poorly water-soluble drugs in the GI tract by forming emulsions with lipids and interacting with intestinal bile micelles (Pharm Res, 2013, 30, 3131–3144; Mol. Pharmaceutics 2020, 17, 3202−3213). The digestion of surfactants depends on various factors, including their quantity, type, and their interaction with other elements like bile salts and lipases. Understanding their digestion kinetics improves comprehension of their impact on absorption of co-administered drugs. This study aimed to investigate the combined effects of surfactants and lipids on drug absorption from intestinal fluids (Fig. 1), with the end goal of predicting the influence of drug-lipid-surfactant interactions on pharmacokinetics.

Methods: A series of in vitro experiments, including analysis of surfactant digestion, and measurement of drug solubility in the fasted and fed state with or without surfactants, were conducted to gather parameters for predicting the absorption of the poorly water-soluble model drug, griseofulvin (GRIS), when co-dosed with lipids (triolein) and surfactants (Tween 80 and Brij 97). Key parameters such as rate constants for digestion, dissolution, permeability into and out of emulsion droplets, and partition coefficients in micellar and oil phases were measured and integrated into a model capturing kinetics of these concurrent processes. Subsequently, predictions from the model were compared with in vivo animal pharmacokinetic (PK) data to evaluate its accuracy.

Results: Drug solubility in simulated intestinal fluids modeling fed and fasted states increased with higher surfactant concentrations, indicating a linear relationship between surfactant concentration and drug solubilization capacity for GRIS (Fig. 2A). Digestion studies indicated that Tween 80 was relatively readily susceptible to digestion, as evidenced by measured fatty acid profiles, whereas the ether-based surfactant Brij 97 was not hydrolyzed over the same period (i.e., no fatty acids were liberated during digestion) (Fig. 2B). Model predictions of the effects of surfactants and triolein on in vivo pharmacokinetics of GRIS are ongoing. However, it is evident qualitatively that Brij 97 has a greater impact on GRIS exposure relative to tween 80 despite both surfactants having similar solubilization capacities (Fig. 2A), suggesting that by remaining undigested, Brij 97 affects GRIS solubility for a longer period compared to Tween 80, ultimately resulting in higher bioavailability when co-administered with Brij 97 vs. Tween 80 (Fig. 3).

Conclusion: Overall, these findings collectively suggest that a computational model incorporating the effect of digestion of surfactants on drug solubility and consequent dissolution kinetics can enhance understanding of the combined effects of surfactants and lipids on drug absorption in the GI tract and ultimately pharmacokinetics, providing a valuable tool in pharmaceutical development.

Acknowledgements: This work was financially supported by the National Institutes of Health (Grant Number R01GM098117) and the National Science Foundation (Grant Number 2015053).


Fig. 1: Schematic representation of key processes affecting oral drug absorption when the drug is dosed in the presence of lipids and surfactants in the GI tract.


Fig. 2: A) Solubility of GRIS in Tween 80- and -Brij 97 containing fasted state solutions. B) Digestion of 5 mM- Tween 80 and -Brij 97 with 1.5 mM pancreatin in the fasted state.


Fig. 3: Oral PK profiles in rats upon dosing gelatin capsules containing 20 mg/kg GRIS in fasted state.