Binding to plasma proteins

Having entered the blood, drugs may bind to the protein molecules that are present in abundance, resulting in the formation of drug-protein complexes. 

The albumin molecule has different binding sites for anionic and cationic ligands, but van der Waals forces also contribute (p.58). The extent of binding correlates with drug hydrophobicity (repulsion of drug by water). 

A decrease in the concentration of albumin (in liver disease, nephrotic syndrome, poor general condition) leads to altered pharmacokinetics of drugs that are highly bound to albumin. 

Plasma protein-bound drugs that are substrates for transport carriers can be cleared from blood at high velocity e.g., p-amino-hippurate by the renal tubule and sulfo-bromophthalein by the liver. Clearance rates of these substances can be used to determine renal or hepatic blood flow. 

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Importance of protein binding for intensity and duration of drug effect 

The hepatocyte secretes biliary fluid into the bile canaliculi (dark green), tubular intercellular clefts that are sealed off from the blood spaces by tight junctions. Secretory activity in the hepatocytes results in movement of fluid towards the canalicular space (A). The hepatocyte has an abundance of enzymes carrying out metabolic functions. These are localized in part in mitochondria, in part on the membranes of the rough (rER) or smooth (sER) endoplasmic reticulum. 

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Disopyr mide. Disopyramide phosphate, a phenylacetamide analogue, is a racemic mixture. The dmg can be adininistered po or iv and is useful in the treatment of ventricular and supraventricular arrhythmias (1,2). After po administration, absorption is rapid and nearly complete (83%). Binding to plasma protein is concentration-dependent (35—95%), but at therapeutic concentrations of 2—4 lg/mL, about 50% is protein-bound. Peak plasma concentrations are achieved in 0.5—3 h. The dmg is metabolized in the fiver to a mono-AJ-dealkylated product that has antiarrhythmic activity. The elimination half-life of the dmg is 4—10 h. About 80% of the dose is excreted by the kidneys, 50% is unchanged and 50% as metabolites 15% is excreted into the bile (1,2). 

Elecainide is weU absorbed and 90% of the po dose is bioavailable. Binding to plasma protein is only 40% and peak plasma concentrations are attained in about 1—6 h. Three to five days may be requited to attain steady-state plasma concentrations when multiple doses are used. Therapeutic plasma concentrations are 0.2—1.0 lg/mL. Elecainide has an elimination half-life of 12—27 h, allowing twice a day dosing. The plasma half-life is increased in patients with renal failure or low cardiac outputs. About 70% of the flecainide in plasma is metabolized by the Hver to two principal metaboUtes. The antiarrhythmic potency of the meta-O-dealkylated metaboUte and the meta-O-dealkylated lactam, relative to that of flecainide is 50 and 10%, respectively. The plasma concentrations of the two metaboUtes relative to that of flecainide are 3—25%. Elecainide is mainly excreted by the kidneys, 30% unchanged, the rest as metaboUtes or conjugates about 5% is excreted in the feces (1,2). 

Acebutolol is well absorbed from the GI tract. It undergoes extensive hepatic first-pass metabohsm. BioavailabiUty of the parent compound is about 40%. The principal metaboflte, A/-acetylacebutolol, has antiarrhythmic activity and appears to be more cardioselective. Binding to plasma proteins is only 26%. Peak plasma concentrations of acebutolol are achieved in 2.5 h, 3.5 h for A/-acetylacebutolol. The elimination half-Hves of acebutolol and its metabohte are 3—4 and 8—13 h, respectively. The compounds are excreted by the kidneys (30—40%) and by the Hver into the bile (50—60%). About 40% of the amount excreted in the urine is unchanged acebutolol, the rest as metabofltes (32). 

The percentage of binding to plasma protein is low for caffeine (35%) and theobromine (15 to 25%), but fairly high for theophylline (55 to 67%). This higher binding of theophylline should be considered when it is used as a prescription drug. 

Essentially as a result of its ability to bind to basic sites, heparin interacts with many proteins.398 Although most of these interactions (such as that with protamine, a basic protein frequently used to neutralize heparin399) are probably not of biological significance, binding to plasma proteins and to proteins exposed on the surface of endothelial cells has an important influence on the circulation system. 

Steroid and thyroid hormones are minimally soluble in the blood. Binding to plasma proteins renders them water soluble and facilitates their transport. Protein binding also prolongs the circulating half-life of these hormones. Because they are lipid soluble, they cross cell membranes easily. As the blood flows through the kidney, these hormones would enter cells or be... 

Above 5 Low solubility and poor oral bioavailability. Erratic absorption. High metabolic liability, although potency may still be high. Basic amines tend to show high to very high Vd (Volume of distribution = ratio of overall tissue binding to plasma protein binding)... 

Protein Binding. The degree to which a chemical binds to plasma proteins will highly influence its distribution. Albumin, the most prominent of the many proteins found in mammalian plasma, carries both positive and negative charges with which a polar compound can associate by electrostatic attraction. As with all such reactions, it can be described by the following equations. The more avidly bound the material, the less will be distributed to surrounding fluids as part of a solution and only that portion that is free in solution will be available for diffusion into the tissues. 

In a series of ten morphine 3-benzoates, large differences in rates of enzymatic hydrolysis were seen [122], In 80% human plasma at pH 7.4 and 37°, the unsubstituted 3-benzoate had a tm value of 0.6 h, whereas esters of 2,6-disubstituted benzoic acid were much more resistant to enzymatic attack (t1/2 ranging from 60 h for the dimethylbenzoate to 300 h for the dichloro-and dimethoxybenzoates). Although these results point to marked steric hindrance, electronic effects cannot be excluded but escape characterization because of the limited series. Furthermore, and as mentioned repeatedly in this text, the possibility of binding to plasma proteins is a complicating factor that should be kept in mind. 

The stability of some prodrugs and mutual prodrugs (8.137 and 8.139, Fig. 13) in human and rat plasma was also examined [175], An approximately tenfold acceleration was noted for the mutual prodrug 8.139 at pH 7.4 and 37° for human plasma (71/2 ca. 45 s) compared to buffer (t1/2 ca. 400 s). This and other evidence indicated that cleavage of these carbamates is enzymatic. In contrast, the A-(2-hydroxyphenyl)carbamates (8.137, Fig. 13) showed two- to threefold increases in t1/2 values in human and rat plasma compared to buffer, indicating the absence of an enzymatic hydrolysis, and modest stabilization due to binding to plasma proteins. 

Pharmacokinetics When administered intravenously, ICG rapidly binds to plasma proteins and is exclusively cleared by the liver, and subsequently secreted into the bile [8]. This forms the basis of the use of ICG for monitoring hepatic blood flow and function. Two pharmacokinetics models, a monoexponential decay, which describes the initial rapid clearance of ICG with a half-life of about 3 minutes (Eq. (1)) and a bi-exponential model, which incorporates the secondary phase clearance with a longer half-life (Eq. (2)), describe total clearance of ICG from plasma [ 132]. For real-time measurements by continuous organ function monitoring, the mono-exponential decay is preferred. 

Stability The marker for GFR measurement should be biologically inert, which implies the absence of binding to plasma proteins, reabsorption in the renal tubule, deleterious effect on renal function, and intact excretion of the filtrate in the urine without degradation. This biological inert criterion, albeit difficult to achieve synthetically, confers an enormous advantage for speedy regulatory approval, especially if small doses are used. 

C17. Curiy, S. H., Theoretical changes in drug distribution residting from changes in binding to plasma proteins and to tLssues. J. Pharm. Pharmacol. 22, 753-757... 

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