Deciphering the Interplay of Multidrug Resistance Protein (MRP) with Drug Substrates: Insights into Pharmacokinetics and Therapeutic Strategies

Arlet Georgina^*
*Correspondence: Arlet Georgina, Department of Chemistry and Biochemistry, University of California, San Diego, CA 92093, USA, Email:

Keywords

Therapeutic strategies • Drug substrates • Drug efficacy • Pharmacokinetics

Introduction

Multidrug resistance (MDR) remains a significant hurdle in the treatment of various diseases, including cancer, infectious diseases, and neurological disorders. While several mechanisms contribute to MDR, the overexpression and enhanced activity of efflux transporters, particularly MRPs, have garnered substantial attention due to their broad substrate specificity and clinical relevance.

MRPs belong to the ATP-binding cassette (ABC) transporter superfamily and are encoded by the ABCC gene family. These membrane proteins are expressed in various tissues, including the liver, kidney, intestine, and bloodbrain barrier (BBB), where they facilitate the efflux of endogenous metabolites, xenobiotics, and drugs. By actively pumping substrates out of cells, MRPs contribute to cellular detoxification and the maintenance of intracellular homeostasis [1].

Literature Review

The substrate specificity of MRPs encompasses a wide range of structurally diverse compounds, including anticancer drugs, antivirals, antibiotics, antihypertensives, and antiepileptics. This broad specificity stems from the flexible binding sites within the transmembrane domains of MRPs, allowing them to accommodate various chemical moieties.

The efflux of drug substrates by MRPs can significantly influence their pharmacokinetic profiles, leading to decreased intracellular accumulation and suboptimal therapeutic outcomes. Furthermore, prolonged exposure to subtherapeutic drug concentrations can promote the selection and expansion of drug-resistant cell populations, exacerbating MDR [2,3].

Mechanisms of drug resistance

Several mechanisms contribute to MDR mediated by MRPs, including

Overexpression: Upregulation of MRPs, either constitutively or in response to drug exposure, enhances efflux activity, reducing intracellular drug concentrations below therapeutic thresholds.

Genetic polymorphisms: Single nucleotide polymorphisms (SNPs) in the ABCC gene family can modulate MRP expression and function, affecting individual susceptibility to MDR and drug response variability.

Co-transport of glutathione and conjugated metabolites: MRPs can actively co-transport glutathione and conjugated metabolites with drug substrates, facilitating their extrusion from cells and conferring resistance [4].

Therapeutic strategies

To overcome MDR mediated by MRPs, several strategies have been proposed, including:

Co-administration of MRP inhibitors: Concurrent administration of MRP inhibitors, such as probenecid, cyclosporine A, and MK-571, can block efflux activity and potentiate the intracellular accumulation of co-administered drugs.

Development of mrp substrate analogs: Designing prodrugs or substrate analogs that evade MRP recognition or exhibit enhanced affinity for uptake transporters can bypass efflux-mediated resistance mechanisms.

Targeted drug delivery systems: Utilizing nanocarriers or liposomes functionalized with MRP-targeting ligands can selectively deliver therapeutic agents to MRP-overexpressing cells, minimizing off-target effects and enhancing drug efficacy [5].

Discussion

Understanding the interplay between multidrug resistance protein (MRP) and its drug substrates is crucial for unraveling pharmacokinetic complexities and devising effective therapeutic strategies. MRPs are pivotal players in drug efflux mechanisms, often leading to reduced drug accumulation in target cells and subsequently diminishing therapeutic efficacy.

The interaction between MRPs and drug substrates impacts various pharmacokinetic parameters, including absorption, distribution, metabolism, and elimination. Enhanced efflux of drugs by MRPs can hinder their absorption across biological barriers, alter their distribution within tissues, and increase their metabolism or excretion, thereby influencing their bioavailability and systemic exposure.

Moreover, the involvement of MRPs in drug resistance poses a significant challenge in cancer chemotherapy and antimicrobial therapy. Overexpression of MRPs in cancer cells confers resistance to multiple chemotherapeutic agents, limiting treatment options and compromising patient outcomes. Similarly, in microbial infections, upregulation of MRPs can confer resistance to antimicrobial agents, impeding the eradication of pathogens [6].

To overcome MRP-mediated drug resistance and enhance therapeutic efficacy, several strategies have been proposed. These include the development of MRP inhibitors to block drug efflux, co-administration of MRP substrates with efflux pump inhibitors, rational drug design to evade MRP recognition, and combination therapies targeting multiple resistance mechanisms simultaneously.

Additionally, understanding the molecular mechanisms underlying MRPdrug interactions facilitates the identification of biomarkers predictive of drug response and resistance, enabling personalized medicine approaches. Furthermore, advances in drug delivery systems, such as nanoparticle-based formulations, hold promise in circumventing MRP-mediated resistance by enhancing drug accumulation at the target site while minimizing efflux.

Conclusion

The interplay between MRPs and drug substrates profoundly influences pharmacokinetics, drug efficacy, and the development of MDR. Understanding the underlying mechanisms of MRP-mediated resistance is crucial for the development of effective therapeutic strategies to circumvent MDR and improve clinical outcomes in various disease settings. Further research into the molecular determinants of MRP-drug interactions and the validation of novel therapeutic approaches holds promise for overcoming this formidable challenge in modern medicine.

Acknowledgement

None.

Conflict of Interest

None.

References

1. Park, Sang-hee. "Smoking and adolescent health." Korean J Pediatr 54 (2011): 401.

   Google Scholar, Crossref, Indexed at

2. Pergolizzi, Joseph, Rainer H. Böger, Keith Budd and Albert Dahan, et al. "Opioids and the management of chronic severe pain in the elderly: Consensus statement of an International Expert Panel with focus on the six clinically most often used World Health Organization Step III opioids (buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone)." Pain practice 8 (2008): 287-313.

   Google Scholar, Crossref, Indexed at

3. Blanco, Ana M., Amparo Perez‐Arago, Sara Fernandez‐Lizarbe and Consuelo Guerri. "Ethanol mimics ligand‐mediated activation and endocytosis of IL‐1RI/TLR4 receptors via lipid rafts caveolae in astroglial cells." J Neurochem 106 (2008): 625-639.

   Google Scholar, Crossref, Indexed at

4. Lane, Katie, John J. Dixon, Denise McKeown and Atholl Johnston, et al. "Using tramadol to measure CYP2D6 metabolism in critically ill adults." Intensive Care Med 40 (2014): 1177-1178.

   Google Scholar, Crossref, Indexed at

5. Ballester, Pura, Javier Muriel and Ana M. Peiró. "CYP2D6 phenotypes and opioid metabolism: The path to personalized analgesia." Expert Opin Drug Metab 18 (2022): 261-275.

   Google Scholar, Crossref, Indexed at

6. Hanke, Mark L. and Tammy Kielian."Toll-like receptors in health and disease in the brain: Mechanisms and therapeutic potential." Clin Sci 121 (2011): 367-387.

   Google Scholar, Crossref