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.

Removal of Cephalosporins by Continuous Arteriovenous Ultrafiltration (CAVU) and Hemofiltration (CAVH)

1989 ◽  
Vol 12 (6) ◽  
pp. 379-383 ◽  
Author(s):  
A.H. Lau ◽  
K. Pyle ◽  
N.O. Kronfol ◽  
C.R. Libertin
Keyword(s):  
Protein Binding ◽  
In Vitro Model ◽  
Plasma Drug ◽  
Flow Rates ◽  
Drug Concentrations ◽  
Vitro Model ◽  
Arterial Plasma ◽  
Kinetics Of ◽  
Venous Plasma

Cephalosporins are used with increasing frequency for sepsis treatment in patients receiving CAVU and CAVH. The different cephalosporins share the same basic molecular structure, yet they exhibit varied extent of plasma protein binding. Different amounts of the antibiotics may be removed by the ultrafiltration procedure because of these variations of physicochemical properties. We evaluated the sieving of eight new cephalosporins across the hemofilter membrane using an in vitro model. Bovine blood was perfused through polysulfone membranes at blood and ultrafiltrate flow rates of 100 and 20 ml/min respectively. Arterial plasma, venous plasma and ultrafiltrate drug concentrations were used to determine sieving coefficients. The sieving coefficients correlated well with the ultrafiltrate-arterial plasma drug concentration ratio (r= 0.679 - 0.972) but poorly with the extent of protein binding. Factors other than protein binding may therefore affect the drug sieving. Based on the findings, it was predicted that 0.2 - 21.9% of the daily cephalosporin dose may be removed by the CAVU and CAVH treatment. The need to alter drug dosages depends on the techniques of the ultrafiltration and hemofiltration procedure, the kinetics of the cephalosporins in patients, the sensitivity of the pathogen and the nature of the infection.

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.

Comparative Systemic Toxicity of Ropivacaine and Bupivacaine in Nonpregnant and Pregnant Ewes 

1995 ◽  
Vol 82 (3) ◽  
pp. 734-740 ◽  
Author(s):  
Alan C. Santos ◽  
Richard G. Arthur ◽  
David Wlody ◽  
Pedro De Armas ◽  
Hisayo O. Morishima ◽  
...  
Keyword(s):  
Protein Binding ◽  
Local Anesthetic ◽  
Systemic Toxicity ◽  
Circulatory Collapse ◽  
Serum Concentrations ◽  
Arterial Blood ◽  
Drug Concentrations ◽  
Constant Rate ◽  
Pregnant Sheep ◽  
Margin Of Safety

Background Ropivacaine is a new amide local anesthetic, having therapeutic properties similar to those of bupivacaine but with a wider margin of safety. Bupivacaine is probably the most commonly used drug in obstetric epidural analgesia, even though laboratory studies have suggested that pregnancy increases the cardiotoxicity of bupivacaine but not of other local anesthetics. The current study was designed to reevaluate, in a random and blinded fashion, the systemic toxicity of bupivacaine and ropivacaine in nonpregnant and pregnant sheep. Methods Chronically prepared nonpregnant and pregnant ewes were randomized to receive an intravenous infusion of ropivacaine or bupivacaine at a constant rate of 0.5 mg.kg-1.min-1 until circulatory collapse. The investigators were blinded to the identity of local anesthetic. Heart rate, arterial blood pressure, and cardiac rhythm were monitored throughout the study. Arterial blood samples were obtained before infusion and at the onset of toxic manifestations, which appeared in the following sequence: convulsions, hypotension, apnea, and circulatory collapse. Serum drug concentrations and protein binding were determined. Blood pH and gas tensions were measured. Results There were no significant differences between non-pregnant and pregnant animals in the doses or serum concentrations of either drug required to elicit toxic manifestations. In nonpregnant animals, similar doses and serum concentrations of ropivacaine and bupivacaine were associated with the onset of convulsions and circulatory collapse. In pregnant ewes, greater doses of ropivacaine as compared to bupivacaine were required to produce convulsions (7.5 +/- 0.5 vs. 5.0 +/- 0.6 mg.kg-1) and circulatory collapse (12.9 +/- 0.8 vs. 8.5 +/- 1.2 mg.kg-1). The corresponding serum concentrations of ropivacaine were similar to those of bupivacaine. Pregnancy did not affect the serum protein binding of either drug. The proportion of animals manifesting a malignant ventricular arrhythmia as the terminal event was similar among all groups. Conclusions The systemic toxicity of ropivacaine or bupivacaine is not enhanced by gestation in sheep. This is in contrast to an earlier study in which the cardiotoxicity of bupivacaine was enhanced during ovine pregnancy. Greater doses of ropivacaine, as compared to bupivacaine, are needed to produce toxic manifestations in pregnant animals.

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.

Effect of pH and inhibitors on beta-amyloid fibril assembly

1996 ◽  
Vol 54 ◽  
pp. 752-753
Author(s):  
Beverly E. Maleeff ◽  
Timothy K. Hart ◽  
Stephen J. Wood ◽  
Ronald Wetzel
Keyword(s):  
Amyloid Fibril ◽  
Peptide Fragment ◽  
Hydrophobic Peptides ◽  
Amyloid Fibril Formation ◽  
Effects Of Ph ◽  
Severity Of The Disease ◽  
Kinetics Of ◽  
The Brain

Alzheimer's disease is characterized post-mortem in part by abnormal extracellular neuritic plaques found in brain tissue. There appears to be a correlation between the severity of Alzheimer's dementia in vivo and the number of plaques found in particular areas of the brain. These plaques are known to be the deposition sites of fibrils of the protein β-amyloid. It is thought that if the assembly of these plaques could be inhibited, the severity of the disease would be decreased. The peptide fragment Aβ, a precursor of the p-amyloid protein, has a 40 amino acid sequence, and has been shown to be toxic to neuronal cells in culture after an aging process of several days. This toxicity corresponds to the kinetics of in vitro amyloid fibril formation. In this study, we report the biochemical and ultrastructural effects of pH and the inhibitory agent hexadecyl-N-methylpiperidinium (HMP) bromide, one of a class of ionic micellar detergents known to be capable of solubilizing hydrophobic peptides, on the in vitro assembly of the peptide fragment Aβ.

Submerged upflow biotower operation and computer simulation

1994 ◽  
Vol 30 (11) ◽  
pp. 143-146
Author(s):  
Ronald D. Neufeld ◽  
Christopher A. Badali ◽  
Dennis Powers ◽  
Christopher Carson
Keyword(s):  
Computer Simulation ◽  
Benzoic Acid ◽  
Computer Model ◽  
Rate Constants ◽  
Batch Mode ◽  
Operational Conditions ◽  
First Order ◽  
Low Concentrations ◽  
Biological Transformation ◽  
Kinetics Of

A two step operation is proposed for the biodegradation of low concentrations (< 10 mg/L) of BETX substances in an up flow submerged biotower configuration. Step 1 involves growth of a lush biofilm using benzoic acid in a batch mode. Step 2 involves a longer term biological transformation of BETX. Kinetics of biotransformations are modeled using first order assumptions, with rate constants being a function of benzoic acid dosages used in Step 1. A calibrated computer model is developed and presented to predict the degree of transformation and biomass level throughout the tower under a variety of inlet and design operational conditions.

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