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

ABSTRACT

Introduction: 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.

Areas covered: 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.

Expert opinion: 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.

KEYWORDS:

• P-glycoprotein
• solubility
• bioavailability
• supersaturation
• spring-and-parachute approach
• lipid-based formulations

Article highlights

• In BCS, orally administered drugs are categorized into 4 classes depending on solubility and permeability. As common properties, P-gp substrate drugs are preferentially absorbed in the duodenum by passive diffusion, and their intestinal absorption can be suppressed at least partly by intestinal P-gp and/or CYP3A. In addition to solubility and permeability, the contribution of intestinal CYP3A-mediated first-pass metabolism, SLC transporter-mediated transport, and high-fat meal effects are clearly different among different BCS class drugs.

• High-fat meals increase the oral bioavailability of BCS Class II drugs while decrease that of Class III drugs but have no effect on BCS Class I drugs. The discrepancy of the meal effect could be derived from the difference in the interaction between drugs and dietary lipoidal and bile components. The lipoidal components can increase the solubility of poorly soluble Class II drugs by decreasing the amount precipitated and increase the oral bioavailability. In contrast, for low permeability-high solubility drugs (BCS Class III), such amphiphiles are not necessary and can in fact decrease the free drug concentrations by incorporation into micelles.

• To increase the oral bioavailability of poorly soluble drugs, the ‘spring-and-parachute-approach’ that generates supersaturation has been proposed. As a ‘spring’, various physicochemical modifications such as particle size reduction, amorphous, cyclodextrin inclusion complexes, liposomal formulations, salts, and water-soluble prodrugs, are available. These modifications increase the dissolution rate of poorly soluble drugs and increase the oral bioavailability by forming supersaturation transiently in vivo. The food effects on their oral bioavailability are ameliorated.

• The ‘spring-and-parachute-approach’ is available in developing lipid-based formulations of poorly soluble drugs. SEDDS can deliver poorly water-soluble drugs as a solution and generate supersaturation in the duodenum. Marketed SEDDS are primarily for BCS Class II/IV P-gp substrate drugs with low solubility and preferential absorption sites in the duodenum. High concentrations of P-gp substrate drugs in the duodenum can increase the passive diffusion by saturating P-gp-mediated efflux transport and CYP3A-mediated intestinal and hepatic first-pass metabolism. By adding appropriate polymers to SEDDS as a ‘parachute’, long-lasting supersaturation can be generated in the duodenum.

• There are many P-gp substrate drugs exhibiting varied oral bioavailability due to low solubility. To attain safer and effective oral bioavailability of such P-gp substrate drugs with preferential absorption sites in the duodenum, lipid-based formulations, such as SMEDDS and/or SNEDDS, are useful. It will be important to study how to increase the unbound free drug concentration at the absorption site by generating supersaturation for a longer period.

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No potential conflict of interest was reported by the author(s).

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Funding

This paper was not funded.