Pharmaceutical Formulations with P-Glycoprotein Inhibitory Effect as Promising Approaches for Enhancing Oral Drug Absorption and Bioavailability

Abstract

P-glycoprotein (P-gp) is crucial in the active transport of various substrates with diverse structures out of cells, resulting in poor intestinal permeation and limited bioavailability following oral administration. P-gp inhibitors, including small molecule drugs, natural constituents, and pharmaceutically inert excipients, have been exploited to overcome P-gp efflux and enhance the oral absorption and bioavailability of many P-gp substrates. The co-administration of small molecule P-gp inhibitors with P-gp substrates can result in drug–drug interactions and increased side effects due to the pharmacological activity of these molecules. On the other hand, pharmaceutically inert excipients, including polymers, surfactants, and lipid-based excipients, are safe, pharmaceutically acceptable, and are not absorbed from the gut. Notably, they can be incorporated in pharmaceutical formulations to enhance drug solubility, absorption, and bioavailability due to the formulation itself and the P-gp inhibitory effects of the excipients. Different formulations with inherent P-gp inhibitory activity have been developed. These include micelles, emulsions, liposomes, solid lipid nanoparticles, polymeric nanoparticles, microspheres, dendrimers, and solid dispersions. They can bypass P-gp by different mechanisms related to their properties. In this review, we briefly introduce P-gp and P-gp inhibitors, and we extensively summarize the current development of oral drug delivery systems that can bypass and inhibit P-gp to improve the oral absorption and bioavailability of P-gp substrates. Since many drugs are limited by P-gp-mediated efflux, this review is helpful for designing suitable formulations of P-gp substrates to enhance their oral absorption and bioavailability.

Formulation and Bioavailability of Novel Mucoadhesive Buccal Films for Candesartan Cilexetil in Rats

“…Anwar et al [ 48 ] created a loaded nanostructured-lipid carrier for CC with bioavailability double that of the oral suspension. The use of P-gp inhibitors is another technique [ 49 ]. Natural P-gp inhibitors (e.g., piperin and quercetin) enhanced CC bioavailability in rats by 68% and 27 and when quercetin and piperin, respectively, were used [ 50 ].…”

A Non-Nutritive Feeding Intervention Alters the Expression of Efflux Transporters in the Gastrointestinal Tract

“…Potent inhibitors for BCRP, MRP2 and P-gp have been described in the literature [39]. These findings suggest that a dosage form could be designed which releases a specific transporter inhibitor to inhibit their expression [40], followed by a drug substrate. Short-term reversibility of the transporter could ensure the normal physiological functioning of the intestinal tract after the dose has been absorbed [38].…”

Pharmacokinetics and Pharmacodynamics of Intranasal Solid Lipid Nanoparticles and Nanostructured Lipid Carriers for Nose-to-Brain Delivery

“…SLNs and NLCs are alternatives to micelles, emulsions, liposomes, and polymeric nanoparticles in drug delivery. They have some distinct advantages that facilitate their wider applications for oral, parenteral, intranasal, ocular, transdermal, and pulmonary drug delivery [ 44 , 45 , 46 ]. The components of SLNs and NLCs are physiologically biocompatible and biodegradable lipids and other excipients that are generally recognized as safe (GRAS), making them safe nano-drug delivery systems [ 47 , 48 ].…”