Prediction of drug concentrations in human skim milk from plasma protein binding and acid-base characteristics.

OBJECTIVE: To report a case of possible neurotoxicity caused by markedly elevated free valproic acid (VPA) plasma concentrations. CASE SUMMARY: A patient with a history of a mixed-type seizure disorder that had been treated with oral VPA 1000 mg four times daily for the previous two years was admitted to the neurology service with the chief complaint of increasing difficulty in walking and involuntary muscle jerks that were new in onset. The patient was hypersomnolent and dysarthric. The total plasma VPA concentration was 103 μg/mL, which was only slightly above the recommended therapeutic range (50–100 μg/mL). VPA free fraction and free plasma concentrations, however, were unexpectedly elevated (26 percent, 26.8 μg/mL, respectively). Further laboratory evaluation revealed a serum albumin concentration of 33 g/L. The neurologic symptoms resolved upon VPA dosage reduction. DISCUSSION: VPA displays concentration-dependent protein binding, resulting in disproportionate increases in drug free fraction with increasing drug concentration. This effect may be magnified in patients with decreased plasma protein-binding capacity. The plasma protein-binding kinetics of VPA are reviewed and the implications for therapeutic drug monitoring are discussed. CONCLUSIONS: It is likely that the markedly elevated free VPA plasma concentrations contributed to the neurologic symptoms displayed in this patient. In patients with decreased albumin concentrations, failure to recognize concentration-dependent protein binding, as well as exclusive reliance upon total drug concentrations, may lead to erroneous pharmacokinetic and therapeutic interpretations.

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Single-dose pharmacokinetics of temocillin in plasma and soft tissues of healthy volunteers after intravenous and subcutaneous administration: a randomized crossover microdialysis trial

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkaa176 ◽

2020 ◽

Vol 75 (9) ◽

pp. 2650-2656 ◽

Cited By ~ 1

Author(s):

Peter Matzneller ◽

Perrin Ngougni Pokem ◽

Arnaud Capron ◽

Edith Lackner ◽

Beatrix Wulkersdorfer ◽

...

Keyword(s):

Soft Tissue ◽

Protein Binding ◽

Healthy Volunteers ◽

Plasma Protein Binding ◽

Plasma Protein ◽

Soft Tissues ◽

Therapeutic Option ◽

Subcutaneous Administration ◽

Intravenous Route ◽

Drug Concentrations

Abstract Background The antibiotic temocillin has recently been rediscovered as a promising therapeutic option against MDR Gram-negative bacteria. However, some aspects of the pharmacokinetic (PK) profile of the drug are still to be elucidated: subcutaneous administration of temocillin might be of interest as an alternative to the intravenous route in selected patients. Similarly, information on the penetration of temocillin into human soft tissues is lacking. Objectives To investigate the feasibility and plasma PK of subcutaneous dosing as well as soft tissue PK of temocillin after intravenous administration to healthy volunteers. Methods Eight healthy volunteers received 2 g of temocillin both as intravenous and subcutaneous infusion in a randomized two-period crossover study. Concentration–time profiles of total temocillin in plasma (after both routes) and of unbound temocillin in plasma, muscle and subcutis (only after intravenous dosing) were determined up to 12 h post-dose. Results Subcutaneous dosing caused some infusion site discomfort but resulted in sustained drug concentrations over time with only slightly decreased overall exposure compared with intravenous dosing. Plasma protein binding of temocillin showed concentration-dependent behaviour and was higher than previously reported. Still, unbound drug concentrations in muscle and subcutis determined by microdialysis markedly exceeded those in plasma, suggesting good tissue penetration of temocillin. Conclusions The subcutaneous administration of temocillin is a valid and feasible alternative to intravenous dosing. With the description of plasma protein binding and soft tissue PK of temocillin in healthy volunteers, this study provides important information that adds to the ongoing characterization of the PK profile of temocillin and might serve as input for PK/PD considerations.

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Artificial Neural Network Modeling for Drug Dialyzability Prediction

Journal of Pharmacy & Pharmaceutical Sciences ◽

10.18433/j35c8b ◽

2013 ◽

Vol 16 (5) ◽

pp. 665 ◽

Cited By ~ 4

Author(s):

Kahina Daheb ◽

Mark L. Lipman ◽

Patrice Hildgen ◽

Julie J Roy

Keyword(s):

Neural Network ◽

Artificial Neural Network ◽

Protein Binding ◽

Plasma Protein Binding ◽

Plasma Protein ◽

Neural Network Modeling ◽

Ann Model ◽

Drug Concentrations ◽

Drug Removal ◽

Artificial Neural

Purpose. The purpose of this study was to develop an artificial neural network (ANN) model to predict drug removal during dialysis based on drug properties and dialysis conditions. Nine antihypertensive drugs were chosen as model for this study. Methods. Drugs were dissolved in a physiologic buffer and dialysed in vitro in different dialysis conditions (UFRmin/UFRmax, with/without BSA). Samples were taken at regular intervals and frozen at -20ºC until analysis. Extraction methods were developed for drugs that were dialysed with BSA in the buffer. Drug concentrations were quantified by high performance liquid chromatography (HPLC) or mass spectrometry (LC/MS/MS). Dialysis clearances (CLDs) were calculated using the obtained drug concentrations. An ANOVA with Scheffe’s pairwise adjustments was performed on the collected data in order to investigate the impact of drug plasma protein binding and ultrafiltration rate (UFR) on CLD. The software Neurosolutions® was used to build ANNs that would be able to predict drug CLD (output). The inputs consisted of dialysis UFR and the herein drug properties: molecular weight (MW), logD and plasma protein binding. Results. Observed CLDs were very high for the majority of the drugs studied. The addition of BSA in the physiologic buffer statistically significantly decreased CLD for carvedilol (p= 0.002) and labetalol (p<0.001), but made no significant difference for atenolol (p= 0.100). In contrast, varying UFR does not significantly affect CLD (p>0.025). Multiple ANNs were built and compared, the best model was a Jordan and Elman network which showed learning stability and good predictive results (MSEtesting = 129). Conclusion. In this study, we have developed an ANN-model which is able to predict drug removal during dialysis. Since experimental determination of all existing drug CLDs is not realistic, ANNs represent a promising tool for the prediction of drug CLD using drug properties and dialysis conditions. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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Parabolic equation relating free and total drug concentrations in cases of nonlinear plasma protein binding

Journal of Pharmaceutical Sciences ◽

10.1002/jps.2600700725 ◽

1981 ◽

Vol 70 (7) ◽

pp. 802-804 ◽

Cited By ~ 7

Author(s):

Harriet L. Behm ◽

John G. Wagner

Keyword(s):

Parabolic Equation ◽

Protein Binding ◽

Plasma Protein Binding ◽

Plasma Protein ◽

Total Drug ◽

Nonlinear Plasma ◽

Drug Concentrations

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Faculty Opinions recommendation of Matched molecular pairs as a guide in the optimization of pharmaceutical properties; a study of aqueous solubility, plasma protein binding and oral exposure.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1046889.496914 ◽

2006 ◽

Author(s):

Michael Gelb

Keyword(s):

Protein Binding ◽

Plasma Protein Binding ◽

Plasma Protein ◽

Aqueous Solubility ◽

Oral Exposure ◽

Matched Molecular Pairs ◽

Pharmaceutical Properties

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Possible therapeutic interventions in COVID-19 induced ARDS by cotinine as an ACE-2 promoter and AT-1R blocker

Infectious Disorders - Drug Targets ◽

10.2174/1871526520666201218153554 ◽

2020 ◽

Vol 20 ◽

Author(s):

Tarun Sharma ◽

Sidharth Mehan

Keyword(s):

Protein Binding ◽

Plasma Protein Binding ◽

Plasma Protein ◽

Distress Syndrome ◽

Therapeutic Interventions ◽

Promising Candidate ◽

Angiotensin Converting Enzyme 2 ◽

Proinflammatory Effect ◽

Pulmonary Permeability

: In these challenging times of the pandemic, as coronavirus disease 2019 (COVID-19) has taken over the planet, its complications such as acute respiratory distress syndrome (ARDS) have the potential to wipe out a large portion of our population. Whereas a serious lack of ventilators, vaccine being months away makes the condition even worse. That's why promising drug therapy is required. One of them was suggested in this article. It is the angiotensin-converting enzyme-2 (ACE-2) to which the COVID-19 virus binds and upon downregulation of which the pulmonary permeability increases and results in the filling of alveoli by proteinaceous fluids, which finally results in ARDS. ARDS can be assisted by angiotensinII type-1 receptor (AT-1R) blocker and ACE-2 upregulator. AT-1R blocker will prevent vasoconstriction, the proinflammatory effect seen otherwise upon its activation. ACE-2 upregulation will ensure less formation of angiotensin II, vasodilatory effects due to the formation of angiotensin (1-7), increased breakdown of bradykinin at lung level. Overall, decreased vasoconstriction of vessels supplying lungs and decreased vasodilation of lung tissues will ensure decreased pulmonary permeability and eventually relieve ARDS. It should also be considered that all components of the reninangiotensin-aldosterone system (RAAS) are located in the lung tissues. A drug with the least plasma protein binding is required to ensure its distribution across these lung tissues. Cotinine appears to be a promising candidate for COVID-19- induced ARDS. It acts across the board and acts as both an AT-1R blocker, ACE-2 upregulator. It also has a weak plasma protein binding that helps to spread through the lung tissues. In this review, we summarized that cotinine, along with COVID-19 virus replication blocker anti-virals, may prove to be a promising therapy for the treatment of COVID-19 induced ARDS.

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Ultrafiltration Method for Plasma Protein Binding Studies and Its Limitations

Processes ◽

10.3390/pr9020382 ◽

2021 ◽

Vol 9 (2) ◽

pp. 382

Author(s):

Camelia-Maria Toma ◽

Silvia Imre ◽

Camil-Eugen Vari ◽

Daniela-Lucia Muntean ◽

Amelia Tero-Vescan

Keyword(s):

Protein Binding ◽

Plasma Protein Binding ◽

Plasma Protein ◽

Specific Binding ◽

Critical Role ◽

Volume Ratio ◽

Binding Studies ◽

Experimental Conditions ◽

Key Aspects

Plasma protein binding plays a critical role in drug therapy, being a key part in the characterization of any compound. Among other methods, this process is largely studied by ultrafiltration based on its advantages. However, the method also has some limitations that could negatively influence the experimental results. The aim of this study was to underline key aspects regarding the limitations of the ultrafiltration method, and the potential ways to overcome them. The main limitations are given by the non-specific binding of the substances, the effect of the volume ratio obtained, and the need of a rigorous control of the experimental conditions, especially pH and temperature. This review presents a variety of methods that can hypothetically reduce the limitations, and concludes that ultrafiltration remains a reliable method for the study of protein binding. However, the methodology of the study should be carefully chosen.

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