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Review
. 2023 Dec 11:14:1308632.
doi: 10.3389/fphys.2023.1308632. eCollection 2023.

Drug transport by red blood cells

Affiliations
Review

Drug transport by red blood cells

Sara Biagiotti et al. Front Physiol. .

Erratum in

  • Corrigendum: Drug transport by red blood cells.
    Biagiotti S, Perla E, Magnani M. Biagiotti S, et al. Front Physiol. 2024 Jul 30;15:1454770. doi: 10.3389/fphys.2024.1454770. eCollection 2024. Front Physiol. 2024. PMID: 39139478 Free PMC article.

Abstract

This review focuses on the role of human red blood cells (RBCs) as drug carriers. First, a general introduction about RBC physiology is provided, followed by the presentation of several cases in which RBCs act as natural carriers of drugs. This is due to the presence of several binding sites within the same RBCs and is regulated by the diffusion of selected compounds through the RBC membrane and by the presence of influx and efflux transporters. The balance between the influx/efflux and the affinity for these binding sites will finally affect drug partitioning. Thereafter, a brief mention of the pharmacokinetic profile of drugs with such a partitioning is given. Finally, some examples in which these natural features of human RBCs can be further exploited to engineer RBCs by the encapsulation of drugs, metabolites, or target proteins are reported. For instance, metabolic pathways can be powered by increasing key metabolites (i.e., 2,3-bisphosphoglycerate) that affect oxygen release potentially useful in transfusion medicine. On the other hand, the RBC pre-loading of recombinant immunophilins permits increasing the binding and transport of immunosuppressive drugs. In conclusion, RBCs are natural carriers for different kinds of metabolites and several drugs. However, they can be opportunely further modified to optimize and improve their ability to perform as drug vehicles.

Keywords: blood distribution; blood-to-plasma ratio; drug transport; pharmacokinetic; red blood cells.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

FIGURE 1
FIGURE 1
Drug partitioning into RBCs. Lipophilic drugs and small molecules can enter the RBC through the lipid bilayer, while hydrophilic compounds can enter via the aqueous channels (in blue) or other transporters such as Glut 1 (in brown). Once in the cytoplasm, drugs can find several binding sites. Among those, we can find hemoglobin, carbonic anhydrase, and immunophilins that possess an affinity for several drugs. RBC partitioning is also affected by drug efflux across several transporters like P-glycoprotein and multidrug resistance-associated protein (MRPs) (in red and yellow, respectively). Hb, hemoglobin; CA-I/II, carbonic anhydrase I and II.
FIGURE 2
FIGURE 2
Sample choice for pharmacokinetic evaluation. Drug distribution strictly affects the pharmacokinetic properties of the same therapeutic agent. Thus, the choice of the most suitable sample for therapeutic drug monitoring is pivotal. In the case of drugs with a blood-to-plasma ratio lesser than 1, plasma is the sample of choice for pharmacokinetic evaluations. On the contrary, when the blood-to-plasma ratio is higher than 1, whole blood is the recommended sample on which the assessment of drug concentration is performed. Either plasma or whole blood is appropriate if the ratio is around 1.
FIGURE 3
FIGURE 3
Engineered RBCs as immunophilin carriers. The figure schematizes how we can increase the drug-binding capacity of RBCs by increasing the concentration of the intracellular receptor (binding site). The example of immunosuppressants and immunophilins is given as a proof-of-concept. The immunophilin FKBP12 is known to bind to the immunosuppressant FK506 (also known as tacrolimus); thus, the overloading of the recombinant protein FKBP12 can increase the affinity for the same drug. The overloading of cyclophilin A can increase the affinity for cyclosporine A. Abbreviation in the figure: FKBP12, FK506-binding protein; CypA, cyclophilin A; CsA, cyclosporine A.

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