ReviewJournal of pharmaceutical sciences2018
Nonlinear Protein Binding: Not What You Think.
Review in Journal of pharmaceutical sciences, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers, 3 of them syntheses that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
19 citing papers in PubMed, 3 syntheses or guidelines pooled it, 33 citations in OpenAlex.
- Re-discover the value of protein binding assessments in hepatic and renal impairment studies and its contributions in drug labels and dose decisions.Clinical and translational science · 2024Pooled it
- An Overview of the Protein Binding of Cephalosporins in Human Body Fluids: A Systematic Review.Frontiers in pharmacology · 2022Pooled it
- Efficacy and safety of high-dose tigecycline for the treatment of infectious diseases: A meta-analysis.Medicine · 2019Pooled it
- Pharmacokinetic and Pharmacodynamic Profiling of Minocycline for Injection following a Single Infusion in Critically Ill Adults in a Phase IV Open-Label Multicenter Study (ACUMIN).Antimicrobial agents and chemotherapy · 2021Trial
- Protein Binding of Cefazolin is Not Saturated in Human Synovial Fluid After Single-Dose Perioperative Antibiotic Prophylaxis.European journal of drug metabolism and pharmacokinetics · 2026Article
- Dose optimization of inhaled tigecycline in humans to overcome inherent adverse events and maximize bacterial clearance using a physiologically-based pharmacokinetic modeling approach.Frontiers in tuberculosis · 2026Article
- Comparative pharmacokinetics of ceftazidime in Siamese crocodiles after intramuscular administration between forelimb and hindlimb.Veterinary research communications · 2025Article
- Preclinical Pharmacokinetic Evaluation of Mithramycin and Mithramycin SA Tryptophan-Conjugated Analog.Pharmaceutics · 2025Article
- Effect of hypoalbuminemia on drug pharmacokinetics.Frontiers in pharmacology · 2025Review
- Free drug percentage of moxidectin declines with increasing concentrations in the serum of marsupials.International journal for parasitology. Parasites and wildlife · 2024Article
- Amphotericin B tissue penetration and pharmacokinetics in healthy andFrontiers in pharmacology · 2024Article
- Comparative Activities of Novel Therapeutic Agents against Molecularly Characterized Clinical Carbapenem-ResistantMicrobiology spectrum · 2023Article
- Why 90% of clinical drug development fails and how to improve it?Acta pharmaceutica Sinica. B · 2022Review
- Model-Informed Drug Development for Anti-Infectives: State of the Art and Future.Clinical pharmacology and therapeutics · 2021Review
- Comparisons of Four Protein-Binding Models Characterizing the Pharmacokinetics of Unbound Phenytoin in Adult Patients Using Non-Linear Mixed-Effects Modeling.Drugs in R&D · 2020Article
- Characteristics of Dolutegravir and Bictegravir Plasma Protein Binding: a First Approach for the Study of Pharmacologic Sanctuaries.Antimicrobial agents and chemotherapy · 2020Article
- Distinguishing Pharmacokinetics of Marketed Nanomedicine Formulations Using a Stable Isotope Tracer Assay.ACS pharmacology & translational science · 2020Article
- Accumulation of TB-Active Compounds in Murine Organs Relevant to Infection byFrontiers in pharmacology · 2020Article
- Interethnic scaling of fraction unbound of a drug in plasma and volume of distribution: an analysis of extrapolation from Caucasians to Chinese.European journal of clinical pharmacology · 2019Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
Nonlinear protein binding is traditionally thought of as an increasing fraction unbound with increasing total drug concentration. In the past several years, research into the protein binding of several tetracyclines has shown that an unexpected and counterintuitive phenomenon has been observed, specifically that of decreasing unbound drug fraction with increasing total concentrations of drug over certain concentration ranges. Although several studies of tigecycline have shown the importance calcium and its chelation may play in the protein-drug interaction, the potential clinical implications and relevance have not been explored. Here, we define typical and atypical nonlinear protein binding, overview protein binding theory, and discuss theoretical implications on pharmacokinetics. Using tigecycline as an example, in silico simulations and calculations show how when atypical nonlinear protein binding is not accounted for free drug exposure, and drug tissue penetration may be overestimated. It is important to revisit the impacts of nonlinearity in protein binding on clinical pharmacokinetics and pharmacodynamics, and ultimately, clinical efficacy. Although this phenomenon could potentially warrant clinical dose adjustment for certain compounds, it also presents a potential opportunity to exploit underlying mechanisms to develop new therapies and better understand molecular interactions of xenobiotics within the physiological system.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.