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On behalf of the team I am pleased to present the second annual 'novel insights into drug transporter sciences review' focused on peer-reviewed articles that were published in the year 2021. In compiling the articles for inclusion, preprints available in 2021 but officially published in 2022 were considered to be in scope. To support this review the contributing authors independently selected one or two articles that were thought to be impactful and of interest to the broader research community. A similar approach as published last year was adopted whereby key observations, methods and analysis of each paper is concisely summarized in the synopsis followed by a commentary highlighting the impact of the paper in understanding drug transporters' role in drug disposition. As the goal of this review is not to provide a comprehensive overview of each paper but rather highlight important findings that are well supported by the data, the reader is encouraged to consult the original articles for additional information. Further, and keeping in line with the goals of this review, it should be noted that all authors actively contributed by writing synopsis and commentary for individual papers and no attempt was made to standardize language or writing styles. In this way, the review article is reflective of not only the diversity of the articles but also that of the contributors. I extend my thanks to the authors for their continued support and also welcome Diane Ramsden and Pallabi Mitra as contributing authors for this issue (Table 1). Table 1. Selected articles for this review. Title Area Authors Source 1. Atorvastatin-associated rhabdomyolysis in a patient with a novel variant of the SLCO1B1 gene: a case report Polymorphism Kiage et al. J Clin Lipidol. 2022;16(1):23–27 2. Quantitation of plasma membrane drug transporters in kidney tissue and cell lines using a novel proteomic approach enabled a prospective prediction of metformin disposition Proteomics Kikuchi et al. Drug Metab Dispos. 2021;49(10):938–946 3. Proteomics-informed prediction of rosuvastatin plasma profiles in patients with a wide range of body weight Proteomics Wegler et al. Clin Pharmacol Ther. 2021;109(3):762–771 4. Performance of plasma coproporphyrin I and III as OATP1B1 biomarkers in humans Biomarker Neuvonen et al. Clin Pharmacol Ther. 2021 Dec;110(6):1622–1632 5. Identification of appropriate endogenous biomarker for risk assessment of multidrug and toxin extrusion protein-mediated drug-drug interactions in healthy volunteers Biomarker Miyake et al. Clin Pharmacol Ther. 2021;109(2):507–516 6. Population pharmacokinetic modeling and simulation to support qualification of pyridoxic acid as endogenous biomarker of OAT1/3 renal transporters Biomarker Ahmad et al. CPT Pharmacometrics Syst Pharmacol. 2021 May;10(5):467–477 7. Acute and chronic effects of rifampin on letermovir suggest transporter inhibition and induction contribute to letermovir Pharmacokinetics Induction/Biomarkers Robbins et al. Clin Pharmacol Ther. 2022;111(3):664–675 8. Exploring the use of serum-derived small extracellular vesicles as liquid biopsy to study the induction of hepatic cytochromes P450 and organic anion transporting polypeptides Induction/Biomarkers Rodrigues et al. Clin Pharmacol Ther. 2021;110(1):248–258 9. Unraveling pleiotropic effects of rifampicin by using physiologically based pharmacokinetic modeling: assessing the induction magnitude of P-glycoprotein-cytochrome P450 3A4 dual substrates Induction Pan et al. CPT Pharmacometrics Syst Pharmacol. 2021;10:1485–1496. 10. Quantification of CYP3A and Drug transporters activity in healthy young, healthy elderly and chronic kidney disease elderly patients by a microdose cocktail approach Clinical pharmacology Rattanacheeworn et al. Front Pharmacol. 2021;12:726669. 11. Quantitative prediction of P-glycoprotein-mediated drug–drug interactions and intestinal absorption using humanized mice DDI Miyake et al. Br J Pharmacol. 2021;178(21):4335–4351. 12. Regulation of OATP1B1 function by tyrosine kinase-mediated phosphorylation Regulation Hayden et al. Clin Cancer Res. 2021;27(15):4301–4310. [ABSTRACT FROM AUTHOR]

1. Accurate predictions of clinical transporter-mediated drug–drug interactions (DDI) fromin vitrodata can be challenging when compounds have poor solubility and/or high nonspecific binding. Additionally, current DDI predictions for compounds with high plasma–protein binding assume that the unbound fraction in plasma is 0.01, if the experimental value is less than 0.01 or cannot be determined. This approach may result in an overestimation of DDI risk. To overcome these challenges, it may be beneficial to conduct inhibition studies under physiologically relevant conditions. 2. Here, IC50values, determined in the presence of 4% bovine serum albumin approximating human plasma albumin concentrations, were successfully used to predict DDI for uptake transporters, OATP1B1/1B3, OCT1/2, OAT1/3 and MATE1/2K. 3. The IC50values of reference inhibitors with 4% bovine serum albumin, considered total IC50, were comparable to the predicted values based on nominal IC50values determined under protein-free conditions and unbound fraction in plasma. Calculation of R-total andCmax/IC50,totalvalues using total plasma exposure and total IC50values explained the clinical DDI or absence of it for these inhibitors. 4. These results suggest that IC50determinations in the presence of 4% albumin can be used, in the context of clinical total exposure, to predict DDI involving uptake transporters. [ABSTRACT FROM PUBLISHER]

The aim of this article is to understand the bereavement of a family as a unit from multiple perspectives. Using qualitative metasynthesis, we described family members’ bereavement experiences from multiple perspectives. The most common perspectives reported were those of parents who had lost their children. No studies reported the perspectives of husbands. Every article explicitly or implicitly referred to a continued connection with the deceased and the effect of this connection on family relationships. This article addresses the importance of focusing on more than one relationship within a family, which should be investigated further in future research. [ABSTRACT FROM PUBLISHER]

An integrated method consisting of a proper orthogonal decomposition (POD)-based reduced-order model (ROM) and a particle filter (PF) is proposed for real-time prediction of an unsteady flow field. The proposed method is validated using identical twin experiments of an unsteady flow field around a circular cylinder for Reynolds numbers of 100 and 1000. In this study, a PF is employed (ROM-PF) to modify the temporal coefficient of the ROM based on observation data because the prediction capability of the ROM alone is limited due to the stability issue. The proposed method reproduces the unsteady flow field several orders faster than a reference numerical simulation based on Navier–Stokes equations. Furthermore, the effects of parameters, related to observation and simulation, on the prediction accuracy are studied. Most of the energy modes of the unsteady flow field are captured, and it is possible to stably predict the long-term evolution with ROM-PF. [ABSTRACT FROM AUTHOR]

1. Transient benign unconjugated hyperbilirubinemia has been observed clinically with several drugs including indinavir, cyclosporine, and rifamycin SV. Genome-wide association studies have shown significant association of OATP1B1 and UGT1A1 with elevations of unconjugated bilirubin, and OATP1B1 inhibition data correlated with clinical unconjugated hyperbilirubinemia for several compounds. 2. In this study, inhibition of OATP1B3 and UGT1A1, in addition to OATP1B1, was explored to determine whether one measure offers value over the other as a potential prospective tool to predict unconjugated hyperbilirubinemia. OATP1B1 and OATP1B3-mediated transport of bilirubin was confirmed and inhibition was determined for atazanavir, rifampicin, indinavir, amprenavir, cyclosporine, rifamycin SV and saquinavir. To investigate the intrinsic inhibition by the drugs, both in vivo Fi (fraction of intrinsic inhibition) and R-value (estimated maximum in vivo inhibition) for OATP1B1, OATP1B3 and UGT1A1 were calculated. 3. The results indicated that in vivo Fi values >0.2 or R-values >1.5 for OATP1B1 or OATP1B3, but not UGT1A1, are associated with previously reported clinical cases of drug-induced unconjugated hyperbilirubinemia. 4. In conclusion, inhibition of OATP1B1 and/or OATP1B3 along with predicted human pharmacokinetic data could be used pre-clinically to predict potential drug-induced benign unconjugated hyperbilirubinemia in the clinic. [ABSTRACT FROM AUTHOR]