Modulation of expression/function of intestinal P-glycoprotein under disease states

ABSTRACT

Introduction: ATP-binding cassette (ABC) transporters, especially P-glycoprotein (P-gp), and various metabolic enzymes, in particular, CYP3A, expressed in the small intestine cooperatively limit the absorption of orally administered P-gp substrate drugs. The expression and/or function of intestinal P-gp, however, is easily modulated by various factors.

Areas covered: Through extensive literature searches primarily utilizing PubMed, the authors reviewed factors that may cause inter- or intra-individual variations of the pharmacokinetics of orally administered P-gp substrate drugs due to the modulation of intestinal P-gp expression/function. The information on P-gp modulating factors can help to develop safer and more reliable oral formulations and pharmacotherapy.

Expert opinion: In clinical pharmacotherapy with orally administered P-gp substrate drugs, the pharmacological action may exhibit a large interindividual variation among patients. Factors modulating intestinal P-gp expression/function listed here include: circadian rhythm (or drug dosing time), drug–drug interactions, formulation/excipients (vehicle, nonionic surfactants), food/supplements, gene polymorphism, obesity, colorectal carcinomas, diarrhea, hepatic failure, inflammation, inflammatory bowel disease, ischemia/reperfusion, organ transplant, renal failure, and others. We will discuss the methods for reducing the effect of modulated intestinal P-gp function on the pharmacokinetics of orally administered P-gp substrate drugs to achieve safer and more reliable oral formulations and pharmacotherapy.

KEYWORDS:

• P-glycoprotein expression
• P-glycoprotein function
• modulation of intestinal P-glycoprotein
• P-glycoprotein substrate drug
• oral bioavailability
• disease
• inflammatory bowel disease
• hepatic failure
• renal failure

Article highlights

• Various factors such as circadian rhythm (or drug dosing time), drug–drug interaction, excipient/formulation, food/supplements, gene polymorphism, obesity, and disease states such as colorectal carcinomas, diarrhea, hepatic failure, inflammation, inflammatory bowel disease, ischemia/reperfusion, organ transplants, renal failure, and others, modify intestinal P-gp expression/function and cause large inter- and intra-individual variations of oral bioavailability of P-gp substrate drugs in vivo.

• In preclinical pharmacokinetic studies, rodents are frequently used. However, species difference between humans and rodents and gender difference should be taken into consideration. For example, GFJ and ginko biloba extracts showed interspecies difference between rats and humans and PEG400 showed gender difference in the modulating effects of intestinal P-gp expression/function in rats. Such differences should be taken into consideration in predicting and analyzing pharmacokinetics in humans.

• The actual in vivo function of P-gp cannot be predicted merely from the expression level of P-gp protein or mRNA under some disease states, possibly due to the presence of endogenous P-gp modulating compounds in biological fluids. Besides TDM, the measurement of P-gp inhibitory effects of biological fluids such as plasma and urine in vitro may be an alternative method to detect the physiological changes of in vivo P-gp function.

• To reduce the modulated effect of intestinal P-gp expression/function on pharmacotherapy, appropriate formulations that secure steady oral bioavailability of P-gp substrate drugs are necessary. Many clinically available orally administered P-gp substrate drugs are reported to be absorbed in the proximal intestine. In order for the drug to be absorbed in the proximal intestine, formulations containing appropriate solubilizers like excipients which can dissolve the active ingredients quickly and completely before reaching the absorption site are desired.

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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.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

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Funding

This paper was not funded.