Lipid formulation strategies for enhancing intestinal transport and absorption of P-glycoprotein (P-gp) substrate drugs:: In vitro/in vivo case studies

The intestinal efflux pump, P-glycoprotein (P-gp), located in the apical membranes of intestinal absorptive cells, can reduce the bioavailability of a wide range of drugs which are substrates for this membrane transporter. In addition to anticancer and anti-HIV drugs, NCEs for other disease indications are P-gp substrates and there is considerable interest in inhibiting P-gp and thus increasing the bioavailability of these molecules. In this review article, an overview of P-gp and its role in drug transport and absorption will be presented first and then formulation strategies to effectively inhibit P-gp will be discussed and compared. These strategies independently and in combination, are: (a) coadministration of another P-gp substrate/specific inhibitor, and (b) incorporation of a nonspecific lipid and/or polymer excipient in the formulation. The first approach, although very effective in inhibiting P-gp, utilizes a second active compound in the formulation and thus imposes regulatory constraints and long development timelines on such combination products. Excipient inhibitors appear to have minimal nonspecific pharmacological activity and thus potential side effects of specific active compound inhibitors can be avoided. Case studies will be presented where specific active compounds, surfactants, polymers, and formulations incorporating these molecules are shown to significantly improve the intestinal absorption of poorly soluble and absorbed drugs as a result of P-gp inhibition and enhanced drug transport in vitro. (c) 2006 Wiley-Liss, Inc.