Guanidinylations of albumin decreased binding capacity of hydrophobic metabolites

Rueth, M.; Lemke, Horst‐Dieter; Preisinger, Christian; Krieter, Detlef H.; Theelen, Wendy; Gajjala, Prathibha R.; Devine, Eric; Zidek, Walter; Jankowski, Joachim; Jankowski, Vera

doi:10.1111/apha.12518

Cited by 40 publications

(52 citation statements)

References 37 publications

(65 reference statements)

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“…New information presented by Rueth et al . in the current issue of Acta Physiologica extends our knowledge regarding decreased binding capacity of albumin of hydrophobic metabolites especially in uraemic patients. The authors were able to use recent developments in selectivity and sensitivity in mass spectrometry to identify and quantify endogenous post‐translational modifications of albumin.…”

mentioning

confidence: 74%

“…The study by Rueth et al . builds on the previous studies, and it showed that the alteration of albumin in CKD patients had a strong impact on total specific and unspecific binding. Thereby, the number of hydrophobic binding sites carrying indoxyl sulphate and especially tryptophan were significantly decreased.…”

mentioning

confidence: 85%

“…The findings by Rueth et al . in this issue of Acta Physiologica showed that albumin from uraemic patients had a post‐translational modifications resulting in lower binding affinity for hydrophobic substances due to conformational changes in an allosteric mechanism. The authors found that uraemia interferes in a significant reduction of hydrophobic binding capacity for substances such as indoxyl sulphate and especially of tryptophan.…”

Section: What Could Be the Consequences?mentioning

confidence: 99%

“…Determination of non‐immunoreactive albumin could predict the onset of microalbuminuria in patients with diabetes mellitus on average 3–4 years earlier than when measured by conventional immunoassays (Comper & Osicka ). The techniques used by Rueth et al . in this issue of Acta Physiologica will help to clarify whether there are similarities between the conformational changes of albumin seen in different diseases and also to clarify how soon changes of albumin develop in patients with progressive kidney disease.…”

Section: What Could Be the Consequences?mentioning

confidence: 99%

“…); however, the molecular reasons have been controversial. In the article by Rueth et al ., the reason is suggested to be due to uraemic metabolites. Conformational changes can also be caused by post‐translational modifications such as oxidation, glycosylation and carbamylation (Meijers et al .…”

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confidence: 99%

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New insight in impaired binding capacity for albumin in uraemic patients

Stegmayr

2015

Acta Physiologica

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. 2015. Guanidinylations of albumin decreased binding capacity of hydrophobic metabolites. Acta Physiol 215, 13-23. New information presented by Rueth et al. in the current issue of Acta Physiologica extends our knowledge regarding decreased binding capacity of albumin of hydrophobic metabolites especially in uraemic patients. The authors were able to use recent developments in selectivity and sensitivity in mass spectrometry to identify and quantify endogenous posttranslational modifications of albumin. The technique enabled the authors to clarify that in uraemic patients, albumin has lower binding affinity due to conformational changes in an allosteric mechanism. A decreased binding capacity of albumin in patients suffering from chronic kidney injury has been described (Watanabe et al. 2012); however, the molecular reasons have been controversial. In the article by Rueth et al., the reason is suggested to be due to uraemic metabolites. Conformational changes can also be caused by post-translational modifications such as oxidation, glycosylation and carbamylation (Meijers et al. 2008).The study by Rueth et al. builds on the previous studies, and it showed that the alteration of albumin in CKD patients had a strong impact on total specific and unspecific binding. Thereby, the number of hydrophobic binding sites carrying indoxyl sulphate and especially tryptophan were significantly decreased.

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confidence: 74%

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confidence: 85%

Section: What Could Be the Consequences?mentioning

confidence: 99%

Section: What Could Be the Consequences?mentioning

confidence: 99%

mentioning

confidence: 99%

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New insight in impaired binding capacity for albumin in uraemic patients

Stegmayr

2015

Acta Physiologica

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Hepatic transporter‐mediated pharmacokinetic drug–drug interactions: Recent studies and regulatory recommendations

Izat

Şahin

2021

Biopharm & Drug Disp

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Transporter‐mediated drug–drug interactions are one of the major mechanisms in pharmacokinetic‐based drug interactions and correspondingly affecting drugs' safety and efficacy. Regulatory bodies underlined the importance of the evaluation of transporter‐mediated interactions as a part of the drug development process. The liver is responsible for the elimination of a wide range of endogenous and exogenous compounds via metabolism and biliary excretion. Therefore, hepatic uptake transporters, expressed on the sinusoidal membranes of hepatocytes, and efflux transporters mediating the transport from hepatocytes to the bile are determinant factors for pharmacokinetics of drugs, and hence, drug–drug interactions. In parallel with the growing research interest in this area, regulatory guidances have been updated with detailed assay models and criteria. According to well‐established preclinical results, observed or expected hepatic transporter‐mediated drug–drug interactions can be taken into account for clinical studies. In this paper, various methods including in vitro, in situ, in vivo, in silico approaches, and combinational concepts and several clinical studies on the assessment of transporter‐mediated drug–drug interactions were reviewed. Informative and effective evaluation by preclinical tools together with the integration of pharmacokinetic modeling and simulation can reduce unexpected clinical outcomes and enhance the success rate in drug development.

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Effect of Chronic Kidney Disease on the Renal Secretion via Organic Anion Transporters 1/3: Implications for Physiologically‐Based Pharmacokinetic Modeling and Dose Adjustment

Tan

Scotcher

Rostami‐Hodjegan

et al. 2022

Clin Pharma and Therapeutics

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There is growing evidence that active tubular secretory clearance (CL s ) may not decline proportionally with the glomerular filtration rate (GFR) in chronic kidney disease (CKD), leading to the overestimation of renal clearance (CL r ) when using solely GFR to approximate disease effect on renal elimination. The clinical pharmacokinetic data of 33 renally secreted OAT1/3 substrates were collated to investigate the impact of mild, moderate, and severe CKD on CL r , tubular secretion and protein binding (f u,p ). The f u,p of the collated substrates ranged from 0.0026 to 1.0 in healthy populations; observed CKD-related increase in the f u,p (up to 2.7-fold) of 8 highly bound substrates (f u,p ≤ 0.2) was accounted for in the analysis. Use of prediction equation based on disease-related changes in albumin resulted in underprediction of the CKD-related increase in f u,p of highly bound substrates, highlighting the necessity to measure protein binding in severe CKD. The critical analysis of clinical data for 33 OAT1/3 probes established that decrease in OAT1/3 activity proportional to the changes in GFR was insufficient to recapitulate effects of severe CKD on unbound tubular secretion clearance. OAT1/3-mediated CL s was estimated to decline by an additional 50% relative to the GFR decline in severe CKD, whereas change in active secretion in mild and moderate CKD was proportional to GFR. Consideration of this additional 50% decline in OAT1/3-mediated CL s is recommended for physiologically-based pharmacokinetic models and dose adjustment of OAT1/3 substrates in severe CKD, especially for substrates with high contribution of the active secretion to CL r .

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Guanidinylations of albumin decreased binding capacity of hydrophobic metabolites

Cited by 40 publications

References 37 publications

New insight in impaired binding capacity for albumin in uraemic patients

New insight in impaired binding capacity for albumin in uraemic patients

Hepatic transporter‐mediated pharmacokinetic drug–drug interactions: Recent studies and regulatory recommendations

Effect of Chronic Kidney Disease on the Renal Secretion via Organic Anion Transporters 1/3: Implications for Physiologically‐Based Pharmacokinetic Modeling and Dose Adjustment

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