Factors and dosage formulations affecting the solubility and bioavailability of P-glycoprotein substrate drugs.

: Expression of P-glycoprotein (P-gp) increases toward the distal small intestine, implying that the duodenum is the preferential absorption site for P-gp substrate drugs. Oral bioavailability of poorly soluble P-gp substrate drugs is low and varied but increases with high-fat meals that supply lipoidal components and bile in the duodenum.: Absorption properties of P-gp substrate drugs along with factors and oral dosage formulations affecting their solubility and bioavailability were reviewed with PubMed literature searches. An overview is provided from the viewpoint of the 'spring-and-parachute approach' that generates supersaturation of poorly soluble P-gp substrate drugs.: The oral bioavailability of P-gp substrate drugs is difficult to predict because of their low solubility, preferential absorption sites, and overlapping substrate specificities with CYP3A4, along with the scattered intestinal P-gp expression/function. To attain high and steady oral bioavailability of poorly soluble P-gp substrate drugs, physicochemical modification of drugs to improve solubility, or oral dosage formulations that generate long-lasting supersaturation in the duodenum, is preferred. In particular, supersaturable lipid-based drug delivery systems that can increase passive diffusion and/or lymphatic absorption are effective and applicable to many poorly soluble P-gp substrate drugs.