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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. [ABSTRACT FROM AUTHOR]

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.

This document is a corrigendum, or correction, for an article titled "Drug transport by red blood cells" published in Frontiers in Physiology. The correction addresses an error in the spelling of one of the author's names, stating that Elena Perla was incorrectly written as Elena Pirla. The authors apologize for the error and clarify that it does not affect the scientific conclusions of the article. The corrigendum also includes a note from the publisher stating that the views expressed in the article are solely those of the authors and do not necessarily represent the views of their affiliated organizations or the publisher. The article is open access and can be cited under the terms of the Creative Commons Attribution License. [Extracted from the article]

Purpose: The number of benzodiazepines appearing as new psychoactive substances (NPS) is continually increasing. Information about the pharmacological parameters of these compounds is required to fully understand their potential effects and harms. One parameter that has yet to be described is the blood-to-plasma ratio. Knowledge of the pharmacodynamics of designer benzodiazepines is also important, and the use of quantitative structure–activity relationship (QSAR) modelling provides a fast and inexpensive method of predicting binding affinity to the GABAA receptor. Methods: In this work, the blood-to-plasma ratios for six designer benzodiazepines (deschloroetizolam, diclazepam, etizolam, meclonazepam, phenazepam, and pyrazolam) were determined. A previously developed QSAR model was used to predict the binding affinity of nine designer benzodiazepines that have recently appeared. Results: Blood-to-plasma values ranged from 0.57 for phenazepam to 1.18 to pyrazolam. Four designer benzodiazepines appearing since 2017 (fluclotizolam, difludiazepam, flualprazolam, and clobromazolam) had predicted binding affinities to the GABAA receptor that were greater than previously predicted binding affinities for other designer benzodiazepines. Conclusions: This work highlights the diverse nature of the designer benzodiazepines and adds to our understanding of their pharmacology. The greater predicted binding affinities are a potential indication of the increasing potency of designer benzodiazepines appearing on the illicit drugs market. [ABSTRACT FROM AUTHOR]

Despite their importance in determining the dosing regimen of drugs in the clinic, only a few studies have investigated methods for predicting blood-to-plasma concentration ratios (Rb). This study established an Rb prediction model incorporating typical human pharmacokinetics (PK) parameters. Experimental Rb values were compiled for 289 compounds, offering reliable predictions by expanding the applicability domain. Notably, it is the largest list of Rb values reported so far. Subsequently, human PK parameters calculated from plasma drug concentrations, including the volume of distribution (Vd), clearance, mean residence time, and plasma protein binding rate, as well as 2702 kinds of molecular descriptors, were used to construct quantitative structure–PK relationship models for Rb. Among the evaluated PK parameters, logVd correlated best with Rb (correlation coefficient of 0.47). Thus, in addition to molecular descriptors selected by XGBoost, logVd was employed to construct the prediction models. Among the analyzed algorithms, artificial neural networks gave the best results. Following optimization using six molecular descriptors and logVd, the model exhibited a correlation coefficient of 0.64 and a root-mean-square error of 0.205, which were superior to those previously reported for other Rb prediction methods. Since Vd values and chemical structures are known for most medications, the Rb prediction model described herein is expected to be valuable in clinical settings. [ABSTRACT FROM AUTHOR]

The blood‐to‐plasma ratio (Rb) is an important property of drug candidates. Rb is applied widely in drug discovery to convert plasma pharmacokinetic parameters to the respective parameters in blood and to develop in vitro–in vivo correlations. Some compounds such as prodrugs, soft drugs, and peptide mimetics are unstable in blood, making accurate in vitro Rb measurement challenging, but necessary. Low temperature often reduces the rate of enzymatic and chemical reactions and increases the stability of labile compounds in biomatrices. In this study, the effects of 4°C on Rb measurement were evaluated using a set of structurally diverse compounds with various binding and red blood cell (RBC) transport mechanisms. The results indicate that a 4°C Rb method provides comparable Rb values to the 37°C method for most compounds and can therefore be applied to measure the Rb of unstable compounds in drug discovery. In some rare cases, when compounds have a high affinity to specific RBC components (e.g., carbonic anhydrase), the 4°C method may underestimate Rb. In these specific cases, the use of appropriate inhibitors to stabilize unstable compounds is recommended. [ABSTRACT FROM AUTHOR]

Evidence‐based pharmacotherapy with carvedilol and enalapril in children suffering from heart failure is insufficient owing to limited pharmacokinetic data. Although a few data sets regarding enalapril, its metabolite enalaprilat and carvedilol in children have been published, pharmacokinetic data on carvedilol metabolites are missing. However, for both drug substances, their active metabolites contribute substantially to drug efficacy. As data can hardly be derived from adults owing to the unknown impacts of enzymatic maturation and ontogeny during childhood, customised assays are important to facilitate paediatric evidence‐based pharmacotherapy. Considering ethical paediatric constraints, a low‐volume liquid chromatography coupled to mass spectrometry (LC–MS/MS) assay was developed using whole blood or plasma for the quantification of enalapril, enalaprilat, carvedilol, O‐desmethyl carvedilol, 4‐ and 5‐hydroxyphenyl carvedilol as well as 3‐ and 8‐hydroxy carvedilol. To facilitate broader applications in adults, the elderly and children, a wide calibration range—between 0.024/0.049 and 50.000 ng/ml—was achieved with good linearity (r ≥ 0.995 for all analytes). In compliance with international bioanalytical guidelines, accuracy, precision, sensitivity and internal standard normalised matrix effects were further successfully validated with the exception of those for 3‐hydroxy carvedilol, which was therefore assessed semi‐quantitatively. Distinct haematocrits did not impact matrix effects or recoveries when analysing whole blood. Blood‐to‐plasma ratios were determined for all analytes to form the basis for pharmacokinetic modelling. Finally, incurred sample reanalysis of paediatric samples confirmed the reproducibility of the developed low‐volume LC–MS/MS method during study sample analysis. The assay facilitates the reliable generation of important data and contributes towards a safe drug therapy in children. [ABSTRACT FROM AUTHOR]

What is known and objective: Dried blood spot (DBS) sampling is a minimally invasive method of blood sampling that enables monitoring of drug concentrations to be more convenient. This study aimed at developing a DBS sampling method for an accurate and precise prediction of radotinib plasma concentrations (Cp) in patients with chronic myeloid leukaemia (CML). Methods: Dried blood spot and venous blood samples were simultaneously collected from fifty CML patients who had been receiving radotinib for at least a week. Radotinib concentrations were measured using a high‐performance liquid chromatographic method with tandem mass spectrometric detection. Unmeasured Cp was predicted directly based on a Deming regression between DBS concentrations (CDBS) and Cp. Unmeasured Cp was also predicted from CDBS corrected by each patient's haematocrit (Hct). Both prediction methods were evaluated for their accuracy and precision using Deming regression and Bland‐Altman analysis. Results and discussion: The Deming regression equation between CDBS and Cp was obtained as follows: Cp = 1.34∙CDBS + 4.26 (r2 =.97). Cp was directly predictable using Cp,pred1 = 1.34∙CDBS + 4.26. With Hct correction, Cp was alternatively predictable using Cp,pred2 = CDBS/ (1–Hct + Hct2). The slopes of Deming regression line between predicted and measured Cp were 0.99 and 1.02 for the direct and Hct‐corrected method, respectively. The mean biases (accuracy) were −0.44% and 1.6% with the 95% limits of agreement (precision) of −22.4% to 21.5% and −20.5% to 23.7%, respectively. More than 93% of predicted and measured Cp pairs had their differences within 20% of the mean of each pair in both methods. What is new and conclusions: Radotinib CDBS are highly correlated with radotinib Cp. Radotinib Cp can be accurately and precisely predicted from CDBS using direct or Hct‐corrected prediction methods. Both appear to be appropriate for the therapeutic monitoring of radotinib in patients with CML. [ABSTRACT FROM AUTHOR]

Therapeutic drug monitoring (TDM) of antiseizure medications (ASMs) represents a valuable tool to establish an appropriate patient therapy, to collect important information about drugs’ interactions and to evaluate patient’s metabolic capabilities. In recent years, a new volumetric absorptive microsampling technique using VAMS® technology and Mitra® devices, consisting of a sampling technique for the collection of fixed-volume capillary blood, was developed. These new devices provide a new home-sampling technique for whole blood that has been spread out to simplify sample collection from finger-pricks. This review is aimed to compare published articles concerning the application of VAMS® in epilepsy and to identify the strengths and improvement points for the TDM of antiseizure medications. VAMS® allowed a minimally invasive blood sampling even in the absence of trained personnel. Good stability data have indicated that storage and delivery can be facilitated only for specific ASMs. Trueness and precision parameters have been evaluated, and the hematocrit (HCT) effect was minimized.

Objective: This work describes a simplified, 96-well plate method for determining the blood-to-plasma concentration ratio (BP ratio) for small molecules., Methods: The need for calibration curves was eliminated using a matrix-matching approach in which blood samples were mixed with blank plasma and plasma samples were mixed with blank blood. As a result, both blood- and plasma-origin samples shared an equivalent matrix ahead of bioanalysis. In the in vitro assay, identical sample matrices were achieved by using the same source of blank plasma and blood., Results: In humans, a good correlation (R2 = 0.84) was observed between the data obtained in this matrix-matching method and literature values for 11 commercial compounds possessing a wide range of logD values across multiple chemical classes. In addition, this method showed good agreement with in vitro BP ratios for 10 proprietary compounds determined radiometrically (R2 = 0.72) in human and preclinical species. Finally, the in vitro matrix matching method compared favorably to BP ratios determined ex vivo for 13 proprietary and literature compounds (R2 = 0.87) in rat., Conclusion: This method, suitable for in vitro and ex vivo BP ratio determinations, is operationally efficient, robust, and a useful improvement upon previously published methods., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Abstract: Drug distribution in blood, defined as drug blood-to-plasma concentration ratio (R b), is a fundamental pharmacokinetic parameter. It relates the plasma clearance to the blood clearance, enabling the physiological interpretation of this parameter. Although easily experimentally determined, R b values are lacking for the vast majority of drugs. We present a systematic approach using mechanistic, partial least squares (PLS) regression and artificial neural network (ANN) models to relate various in vitro and in silico molecular descriptors to a dataset of 93 drug R b values collected in the literature. The ANN model resulted in the best overall approach, with r 2 =0.927 and r 2 =0.871 for the train and the test sets, respectively. PLS regression presented r 2 =0.557 for the train and r 2 =0.656 for the test set. The mechanistic model provided the worst results, with r 2 =0.342 and, additionally, is limited to drugs with a basic ionised group with pKa<7. The ANN model for drug distribution in blood can be a valuable tool in clinical pharmacokinetics as well as in new drug design, providing predictions of R b with a percentage of correct values within a 1.25-fold error of 86%, 84% and 87% in the train, test and validation set of data. [Copyright &y& Elsevier]

Abstract: Topiramate (TPM) is a broad-spectrum antiepileptic drug with various mechanisms of action including an inhibitory effect on some isozymes of carbonic anhydrase (CA). Binding to CA-I and CA-II, which are highly concentrated in erythrocytes, may affect drug pharmacokinetics. Consequently, the objectives of this study were: (a) to comparatively assess TPM pharmacokinetics in healthy subjects, based on plasma and whole blood data, by simultaneously measuring TPM concentrations in plasma and whole blood following different therapeutic doses; (b) to rigorously establish the affinity of TPM for CA-I and CA-II in order to gain insight into how binding to these isozymes in erythrocytes influences TPM pharmacokinetics. TPM (100, 200 and 400mg, single dose) was given in a randomized three-way crossover design to 27 healthy subjects and the drug concentrations in plasma and whole blood were simultaneously measured for 168h after dosing. The pharmacokinetics of TPM in plasma was linear, but TPM clearance from whole blood increased with increasing dose. At low therapeutic concentrations, the blood-to-plasma ratio for TPM decreased from 8 to 2 as its concentration increased, indicating a substantial and saturable binding of TPM to erythrocytes. The kinetics (dissociation binding constant –K d and maximum binding rate –B max) of the binding of TPM to erythrocytes was determined from the measured concentrations of TPM in whole blood and plasma. This analysis indicated the existence of two binding sites with K d values of 0.54 and 140μM, and B max values of 22 and 124μmol/L of erythrocyte volume, respectively. These B max values are similar to literature values for the molar concentration of human CA-II (14–25μmol/L) and CA-I (115–125μmol/L). TPM inhibition constant (K i) values for the inhibition of purified human CA obtained using assays based on CO2 hydration or 4-nitrophenylacetate hydrolysis were 0.62 and 0.49μM for CA-II, and 91 and 93μM for CA-I. The results of these studies indicate that virtually all of the binding of TPM to erythrocytes is attributable to CA-I and CA-II. Because CA-I and CA-II are highly concentrated in erythrocytes, a large portion of TPM in whole blood is bound and serves as a depot. This contributes to the lower oral clearance (CL/F), apparent volume of distribution (Vss/F) and longer half-life (t 1/2) that TPM has in blood compared to the CL/F, Vss/F and t 1/2, estimated from plasma data. The difference between TPM blood and plasma pharmacokinetics was more profound at low doses (≤100mg/day). [Copyright &y& Elsevier]

Therapeutic drug monitoring (TDM) of antiseizure medications (ASMs) represents a valuable tool to establish an appropriate patient therapy, to collect important information about drugs' interactions and to evaluate patient's metabolic capabilities. In recent years, a new volumetric absorptive microsampling technique using VAMS® technology and Mitra® devices, consisting of a sampling technique for the collection of fixed-volume capillary blood, was developed. These new devices provide a new home-sampling technique for whole blood that has been spread out to simplify sample collection from finger-pricks. This review is aimed to compare published articles concerning the application of VAMS® in epilepsy and to identify the strengths and improvement points for the TDM of antiseizure medications. VAMS® allowed a minimally invasive blood sampling even in the absence of trained personnel. Good stability data have indicated that storage and delivery can be facilitated only for specific ASMs. Trueness and precision parameters have been evaluated, and the hematocrit (HCT) effect was minimized. [ABSTRACT FROM AUTHOR]