Protein Binding: What Does it Mean?

DICP ◽  
1989 ◽  
Vol 23 (7-8) ◽  
pp. S27-S31 ◽  
Author(s):  
Richard T. Scheife
Keyword(s):  
Protein Binding ◽  
Plasma Proteins ◽  
Clinical Importance ◽  
General Rule ◽  
Drug Concentrations ◽  
Percent Protein ◽  
Bound Drug ◽  
Total Concentrations ◽  
Better Than

Protein binding can enhance or detract from a drug's performance. As a general rule, agents that are minimally protein bound penetrate tissue better than those that are highly bound, but they are excreted much faster. Among drugs that are less than 80–85 percent protein bound, differences appear to be of slight clinical importance. Agents that are highly protein bound may, however, differ markedly from those that are minimally bound in terms of tissue penetration and half-life. Drugs may bind to a wide variety of plasma proteins, including albumin. If the percentage of protein-bound drug is greater when measured in human blood than in a simple albumin solution, the clinician should suspect that the agent may be bound in vivo to one of these “minority” plasma proteins. The concentration of several plasma proteins can be altered by many factors, including stress, surgery, liver or kidney dysfunction, and pregnancy. In such circumstances, free drug concentrations are a more accurate index of clinical effect than are total concentrations. Formulary committees must grasp the clinical significance of qualitative and quantitative differences in protein binding when evaluating competing agents.

Kinetics of protein binding determine rates of uptake of drugs by brain

1986 ◽  
Vol 251 (6) ◽  
pp. R1212-R1220 ◽  
Author(s):  
P. J. Robinson ◽  
S. I. Rapoport
Keyword(s):  
Protein Binding ◽  
Rate Constants ◽  
Plasma Proteins ◽  
Numerical Solutions ◽  
Free Drug ◽  
Arterial Blood ◽  
Drug Concentrations ◽  
Analytical Expressions ◽  
Kinetics Of ◽  
The Brain

A mathematical model describing the kinetics of binding and release of substances by plasma proteins is presented. The effects of protein binding on the uptake of substances such as drugs from the capillary network of the brain are discussed. The model assumes equilibration between bound and free forms of drug in arterial blood and incorporates the on-off rate constants for the drug-protein complex and rate constants for passage of free drug across the blood-brain barrier and for drug metabolism in the brain. Regional cerebral blood flow and the related capillary transit time are important parameters in the model. Analytical expressions for bound and free drug concentrations and for the net extraction of drug are derived where practicable, and numerical solutions also are presented. Effects of changes in the total drug and protein concentrations in the plasma are discussed with special reference to the uptake of bilirubin by the brain.

scholarly journals Effect of Ertapenem Protein Binding on Killing of Bacteria

2004 ◽  
Vol 48 (9) ◽  
pp. 3419-3424 ◽  
Author(s):  
David E. Nix ◽  
Kathryn R. Matthias ◽  
Emily C. Ferguson
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Activity ◽  
Protein Binding ◽  
Human Serum ◽  
High Performance ◽  
Enterobacter Cloacae ◽  
Free Drug ◽  
Drug Concentrations ◽  
Kill Rate ◽  
Total Concentrations

ABSTRACT The effect of protein binding on the antimicrobial activity of ertapenem was evaluated using the bacterial kill rate and concentration-response studies. Various proportions of human serum were utilized to determine the total and free-drug concentrations using a validated high-performance liquid chromatography assay. The MICs and kill curves were determined for test isolates of Enterobacter cloacae and Staphylococcus aureus at various percentages of human serum. The killing of bacteria was analyzed in relation to the free and total concentrations of ertapenem at various proportions of human serum. It was determined that unbound ertapenem was responsible for the antimicrobial activity against the test isolates.

scholarly journals Novel Method To Assess Antiretroviral Target Trough Concentrations UsingIn VitroSusceptibility Data

2012 ◽  
Vol 56 (11) ◽  
pp. 5938-5945 ◽  
Author(s):  
Edward P. Acosta ◽  
Kay L. Limoli ◽  
Lan Trinh ◽  
Neil T. Parkin ◽  
Jennifer R. King ◽  
...  
Keyword(s):  
Protein Binding ◽  
Serum Protein ◽  
Drug Exposure ◽  
Integrase Inhibitor ◽  
Drug Susceptibility ◽  
Serum Protein Binding ◽  
Drug Concentrations ◽  
Antiretroviral Drug

ABSTRACTDurable suppression of HIV-1 replication requires the establishment of antiretroviral drug concentrations that exceed the susceptibility of the virus strain(s) infecting the patient. Minimum plasma drug concentrations (Ctrough) are correlated with response, but determination of targetCtroughvalues is hindered by a paucity ofin vivoconcentration-response data. In the absence of these data,in vitrosusceptibility measurements, adjusted for serum protein binding, can provide estimations of suppressivein vivodrug concentrations. We derived serum protein binding correction factors (PBCF) for protease inhibitors, nonnucleoside reverse transcriptase inhibitors, and an integrase inhibitor by measuring the effect of a range of human serum concentrations onin vitrodrug susceptibility measured with the PhenoSense HIV assay. PBCFs corresponding to 100% HS were extrapolated using linear regression and ranged from 1.4 for nevirapine to 77 for nelfinavir. Using the mean 95% inhibitory concentration (IC95) for ≥1,200 drug-susceptible viruses, we calculated protein-bound IC95(PBIC95) values. PBIC95values were concordant with the minimum effectiveCtroughvalues that were established in well-designed pharmacodynamic studies (e.g., indinavir, saquinavir, and amprenavir). In other cases, the PBIC95values were notably lower (e.g., darunavir, efavirenz, and nevirapine) or higher (nelfinavir and etravirine) than existing target recommendations. The establishment of PBIC95values as described here provides a convenient and standardized approach for estimation of the minimum drug exposure that is required to maintain viral suppression and prevent the emergence of drug-resistant variants, particularly whenin vivoconcentration-response relationships are lacking.

scholarly journals 1389. Pharmacokinetic/Pharmacodynamic (PK/PD) Evaluation of a Novel Aminomethylcycline Antibiotic, KBP-7072, in the Neutropenic Murine Pneumonia Model Against S. aureus (SA) and S. pneumoniae (SPN)

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S426-S426 ◽  
Author(s):  
Alexander J Lepak ◽  
Miao Zhao ◽  
Qingmei Liu ◽  
Ping Wang ◽  
Yanli Wang ◽  
...  
Keyword(s):  
Dose Range ◽  
Research Support ◽  
Response Data ◽  
Drug Concentrations ◽  
Spectrum Activity ◽  
Dose Dependent ◽  
Free Plasma ◽  
Total Concentrations ◽  
Broad Spectrum Activity

Abstract Background KBP-7072 is a novel aminomethylcycline antibiotic with broad-spectrum activity that includes organisms with drug-resistance to β-lactams and tetracyclines. We examined the PK/PD relationship between KBP-7072 drug exposures and treatment effect using a neutropenic murine pneumonia model against a diverse group of SA and SPN. Methods Five SAs (three MRSAs) and six SPNs (three PCNs NS, two TetR) strains were used. MICs were determined by CLSI Methods. Plasma and ELF PK was determined after SC dosing (range 1–256 mg/kg). Lung burden was assessed by CFU counts at the beginning and end of therapy (24 hours). Infected mice were treated with KBP-7072 by SC route: SA dose range 0.25–64 mg/kg/6 hours, SPN dose range 0.06–16 mg/kg/6 hours. The Emax Hill equation was used to model the dose–response data to the PK/PD index AUC/MIC. The magnitude of the PK/PD index (plasma free and ELF total concentrations) associated with net stasis, 1- and 2-log kill were determined in the pneumonia model for all strains. Results SA MICs were 0.25 mg/L for all isolates and SPN MICs were 0.008–0.016 mg/L. Plasma PK of KBP-7072 included: Cmax 0.12–25.2 mg/L, AUC0-∞ 1.1–234 mg hour/L, T1/2 3.2–4.6 h. ELF PK by urea correction methods included: Cmax 0.06–13.3 mg/L, AUC0-∞ 0.4–95 mg hour/L, T1/2 3.1–4 hours. ELF penetration based on free plasma drug concentrations (77.5% bound) ranged from 82 to 238%. AUC was linear over the dose range (R2 = 0.99). Potent dose-dependent cidal activity (3–5 log kill) was observed against all strains. AUC/MIC was a robust predictor of efficacy (SA R2 = 0.89, SPN R2 0.80). Median static, 1- and 2-log kill AUC/MIC values are shown in the table. Conclusion KBP-7072 demonstrated potent in vivo efficacy against SA and SPN, including strains with elevated minocycline MIC and β-lactam resistance, in the neutropenic murine pneumonia model. A 3–5 log kill was observed and AUC/MIC was strongly associated with efficacy. The AUC/MIC target for net stasis was comparable between SA and SPN at a plasma fAUC/MIC target of ~1 and ELF AUC/MIC target ~2. Cidal targets were similarly very low. All targets were numerically lower than comparative tetracyclines. These results should prove useful for clinical dosing regimen optimization. Disclosures A. J. Lepak, KBP Biosciences: Research Contractor, Research support. Q. Liu, KBP Biosciences: Employee, Salary. P. Wang, KBP Biosciences: Employee, Salary. Y. Wang, KBP Biosciences: Employee, Salary. J. C. Bader, KBP Biosciences: Research Contractor, Research support. P. G. Ambrose, KBP Biosciences: Research Contractor, Research support. D. R. Andes, KBP Biosciences: Research Contractor, Research support.

Effect of Salicylate on the Fate of Bishydroxycoumarin in the Rat

1973 ◽  
Vol 51 (3) ◽  
pp. 205-212 ◽  
Author(s):  
B. H. Thomas ◽  
B. B. Coldwell ◽  
H. S. Buttar ◽  
W. Zeitz
Keyword(s):  
Plasma Proteins ◽  
Initial Rate ◽  
The Other ◽  
Fecal Excretion ◽  
Distribution Study ◽  
Tissue Distribution Study ◽  
Bound Drug ◽  
Lung And Kidney

Salicylate increased the rate of elimination of 14C-bishydroxycoumarin from the blood during the first 7 h after administration. A tissue distribution study showed most of the radioactivity to be found in liver, blood, lung, and kidney. Salicylate treatment increased the concentration of radioactivity in the liver and decreased it in blood, but had little effect in the other tissues. Biliary excretion of radioactivity was increased from 12.3 ± 2.7 to 29.3 ± 2.5% of the dose in the 0–6 h period by salicylate. Total urinary and fecal excretion was little affected. An in vitro plasma protein study showed that salicylate displaces bound bishydroxycoumarin. A similar effect was observed in vivo. It is concluded that salicylate increases the initial rate of bishydroxycoumarin elimination by displacing some of the bound drug from plasma proteins, thereby facilitating uptake into the liver where the drug is metabolized and excreted.

scholarly journals Fast In Vivo Microextraction: A New Tool for Clinical Analysis

2006 ◽  
Vol 52 (4) ◽  
pp. 708-715 ◽  
Author(s):  
Florin Marcel Musteata ◽  
Mihaela L Musteata ◽  
Janusz Pawliszyn
Keyword(s):  
Solid Phase ◽  
Clinical Analysis ◽  
Correlation Factor ◽  
Direct Extraction ◽  
Plasma Analysis ◽  
Drug Concentrations ◽  
Flowing Blood ◽  
Exogenous Compounds ◽  
Total Concentrations

Abstract Background: We sought to develop a technique with the potential to partly replace current methods of analysis based on blood draws. To achieve this goal, we developed an in vivo microextraction technique that is faster than conventional methods, interferes minimally with the investigated system, minimizes errors associated with sample preparation, and limits exposure to hazardous biological samples. Methods: Solid-phase microextraction devices based on hydrophilic polypyrrole and polyethylene glycol coatings were used for direct extraction of drugs from the flowing blood of beagle dogs, over a period of 8 h. The drugs extracted on the probes were subsequently quantified by liquid chromatography coupled to tandem mass spectrometry. Two calibration strategies—external and standard on the fiber—were used to correlate the amount extracted with the in vivo concentration. Results: Diazepam and its metabolites were successfully monitored over the course of a pharmacokinetic study, repeated 3 times on 3 beagles. The fast microextraction technique was validated by comparison with conventional plasma analysis, and a correlation factor of 0.99 was obtained. In addition to total concentrations, the method was useful for determining free drug concentrations. Conclusions: The proposed technique has several advantages and is suitable for fast clinical analyses. This approach could be used not only for drugs, but for any other endogenous or exogenous compounds.

scholarly journals Protein Binding of First-Line Antituberculosis Drugs

2018 ◽  
Vol 62 (7) ◽  
Author(s):  
Wael A. Alghamdi ◽  
Mohammad H. Al-Shaer ◽  
Charles A. Peloquin
Keyword(s):  
Plasma Concentration ◽  
Protein Binding ◽  
Plasma Proteins ◽  
Plasma Concentrations ◽  
Real Life ◽  
Clinical Samples ◽  
Plasma Samples ◽  
First Line ◽  
Case Scenario ◽  
Drug Concentrations

ABSTRACT The 4-drug regimen of rifampin, isoniazid, pyrazinamide, and ethambutol is an inexpensive, reliable option for treating patients with drug-susceptible tuberculosis (TB). Its efficacy could be further improved by determining the free drug concentrations in plasma, knowing that only the unbound drug can freely penetrate to the tissues. Using an ultrafiltration technique, we determined the protein binding (PB) extent and variability of the first-line anti-TB drugs when given simultaneously to TB patients, representing a real-life case scenario. We used clinical samples routinely received by our laboratory. Plasma proteins were also measured. A protein-free medium was used to determine the nonspecific binding. Plasma samples from 22 patients were included, of which plasma proteins were measured for 18 patients. The median PB was determined for rifampin (88%; range, 72 to 91%), isoniazid (14%; range, 0 to 34%), pyrazinamide (1%; range, 0 to 7%), and ethambutol (12%; range, 4 to 24%). Plasma proteins were not found to be significant predictors for the PB of first-line anti-TB drugs. Rifampin PB was positively correlated with its plasma concentration ( P value = 0.0051). Conversely, isoniazid PB was negatively correlated with its plasma concentration ( P value = 0.0417). Age was found to have a significant effect on isoniazid PB ( P value = 0.0376). No correlations were observed in pyrazinamide or ethambutol. In conclusion, we have determined variable PB of rifampin, isoniazid, pyrazinamide, and ethambutol in patient plasma samples, with median values of 88, 14, 1, and 12%, respectively. In this small study, PB of rifampin and that of isoniazid are dependent on their plasma concentrations.

Purification of the Antihemophilic Factor by Gel Filtration on Agarose

1969 ◽  
Vol 22 (03) ◽  
pp. 577-583 ◽  
Author(s):  
M.M.P Paulssen ◽  
A.C.M.G.B Wouterlood ◽  
H.L.M.A Scheffers
Keyword(s):  
Factor Viii ◽  
Plasma Proteins ◽  
Large Scale ◽  
Gel Filtration ◽  
Large Scale Preparation ◽  
Scale Preparation ◽  
Antihemophilic Factor

SummaryFactor VIII can be isolated from plasma proteins, including fibrinogen by chromatography on agarose. The best results were obtained with Sepharose 6B. Large scale preparation is also possible when cryoprecipitate is separated by chromatography. In most fractions containing factor VIII a turbidity is observed which may be due to the presence of chylomicrons.The purified factor VIII was active in vivo as well as in vitro.

Methodological Approaches to Evaluate Fetal Drug Exposure

2019 ◽  
Vol 25 (5) ◽  
pp. 496-504 ◽  
Author(s):  
Naïm Bouazza ◽  
Frantz Foissac ◽  
Déborah Hirt ◽  
Saïk Urien ◽  
Sihem Benaboud ◽  
...  
Keyword(s):  
Cord Blood ◽  
Drug Exposure ◽  
Placental Transfer ◽  
Ex Vivo ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Pbpk Models ◽  
Drug Concentrations ◽  
Fetal Drug Exposure

Background: Drug prescriptions are usual during pregnancy, however, women and their fetuses still remain an orphan population with regard to drugs efficacy and safety. Most xenobiotics diffuse through the placenta and some of them can alter fetus development resulting in structural abnormalities, growth or functional deficiencies. Methods: To summarize the different methodologies developed towards the prediction of fetal drug exposure. Results: Neonatal cord blood concentration is the most specific measurement of the transplacental drug transfer at the end of pregnancy. Using the cord blood and mother drug concentrations altogether, drug exchanges between the mother and fetus can be modeled and quantified via a population pharmacokinetic analysis. Thereafter, it is possible to estimate the fetus exposure and the fetus-to-mother exposure ratio. However, the prediction of placental transfer before any administration to pregnant women is desirable. Animal studies remain difficult to interpret due to structural and functional inter-species placenta differences. The ex-vivo perfusion of the human placental cotyledon is the method of reference to study the human placental transfer of drugs because it is thought to mimic the functional placental tissue. However, extrapolation of data to in vivo situation remains difficult. Some research groups have extensively worked on physiologically based models (PBPK) to predict fetal drug exposure and showed very encouraging results. Conclusion: PBPK models appeared to be a very promising tool in order to predict fetal drug exposure in-silico. However, these models mainly picture the end of pregnancy and knowledge regarding both, development of the placental permeability and transporters is strongly needed.

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