Considerations for Determining Direct Versus Indirect Functional Effects of Solubilizing Excipients on Drug...

Excipients used in drug formulations at clinically safe levels have been considered to be pharmacologically inert; however, numerous studies have suggested that many solubilizing agents may modulate drug transporter activities and intestinal absorption. Here, the reported interactions between various solubilizing excipients and drug transporters are evaluated to consider various potential underlying mechanisms. This forms the basis for debate in the field in regard to whether or not the effects are based on "direct" interactions or "indirect" consequences arising from the role of the excipients. For example, an increase in apparent drug solubility can give rise to saturation of transporters according to Michaelis-Menten kinetics. This is also drawing the attention of regulatory agencies as they seek to understand the role of formulation additives. The continued application of excipients as a tool in solubility enhancement is crucial in the drug development process, creating a need for additional data to verify the proposed mechanism behind these changes. A literature review is provided here with some guidance on other factors that should be considered to delineate the effects that arise from direct physiological interactions or indirect effects. The results of such studies may aid the rational design of bioavailability-enhancing formulations.