Xanthones as P-glycoprotein modulators and their impact on drug bioavailability

ABSTRACT

Introduction: P-glycoprotein (P-gp) is an important efflux pump responsible for the extruding of many endogenous and exogenous substances out of the cells. P-gp can be modulated by different molecules – including xanthone derivatives – to surpass the multidrug resistance (MDR) phenomenon through P-gp inhibition, or to serve as an antidotal strategy in intoxication scenarios through P-gp induction/activation.

Areas covered: This review provides a perspective on P-gp modulators, with particular focus on xanthonic derivatives, highlighting their ability to modulate P-gp expression and/or activity, and the potential impact of these effects on the pharmacokinetics, pharmacodynamics and toxicity of P-gp substrates.

Expert opinion: Xanthones, of natural or synthetic origin, are able to modulate P-gp, interfering with its protein synthesis or with its mechanism of action, by decreasing or increasing its efflux capacity. These modulatory effects make the xanthonic scaffold a promising source of new derivatives with therapeutic potential. However, the mechanisms beyond the xanthones-mediated P-gp modulation and the chemical characteristics that make them more potent P-gp inhibitors or inducers/activators are still understudied. Furthermore, a new window of opportunity exists in the neuropathologies field, where xanthonic derivatives with potential to modulate P-gp should be further explored to optimize the prevention/treatment of brain pathologies.

GRAPHICAL ABSTRACT

KEYWORDS:

• Xanthones
• P-glycoprotein
• modulation
• induction
• activation
• inhibition
• inducers
• activators
• inhibitors
• pharmacokinetics

Article highlights

• P-glycoprotein (P-gp) is an efflux protein that binds and transports a wide range of substrates, including drugs, and the modulation of its expression and/or activity by specific compounds can be used in therapeutic context.

• Xanthones are naturally occurring compounds with several pharmacological activities, including the ability to modulate P-gp expression and/or activity.

• P-gp inhibition by xanthone derivatives has been used to surpass the multidrug resistance (MDR) phenomenon and increase the bioavailability of a drug.

• P-gp induction/activation by xanthone derivatives has been used as a mechanism of cellular defense against toxic compounds.

• Thioxanthones – synthetic compounds related to the xanthonic scaffold – are promising molecules for P-gp modulation.

• The xanthonic scaffold is a promising source of new P-gp inhibitors, inducers and activators that can be further explored to significantly improve MDR reversal or, alternatively, to significantly reduce the intracellular accumulation of harmful P-gp substrates.

This box summarizes key points contained in the article.

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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.

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

The work was also supported by FCT - Foundation for Science and Technology within the scope of UIDB/04423/2020, UIDP/04423/2020, and under the project PTDC/SAU-PUB/28736/2017 (reference POCI-01-0145-FEDER-028736), and co-financed by COMPETE 2020, Portugal 2020 and the European Union through the ERDF and by FCT through national funds.