Sulfonamides protein binding

In subsequent studies attempting to find a correlation of physicochemical properties and antimicrobial activity, other parameters have been employed, such as Hammett O values, electronic distribution calculated by molecular orbital methods, spectral characteristics, and hydrophobicity constants. No new insight on the role of physiochemical properties of the sulfonamides has resulted. Acid dissociation appears to play a predominant role, since it affects aqueous solubiUty, partition coefficient and transport across membranes, protein binding, tubular secretion, and reabsorption in the kidneys. An exhaustive discussion of these studies has been provided (10). 

Sulfaphenazole (684) and sulfazamet (685) are both examples of relatively short acting sulfonamides (B-80MI40406) and their antibacterial activity has been tested against Escherichia coli, the former being more effective than the latter. Sulfaphenazole also displaces sulfonyl ureas from protein binding sites on human serum albumin and consequently increases the concentration of the free (active) drug and produces a more intense reaction that may result in hypoglycemia. 

M) for plasma proteins than for their specific binding sites (receptors). In the range of therapeutically relevant concentrations, protein binding of most drugs increases linearly with concentration (exceptions salicylate and certain sulfonamides). 

Newbould and Kilpatrick (N3) found that addition of plasma to the fluid perfusing a rabbit liver preparation reduced the rate of acetylation of two long-acting sulfonamides and that the rate of metabolism was dependent on the concentration of unbound drug. Anton and Boyle (A8) and Wiseman and Nelson (W15) using data from both in vitro and in vivo techniques reported a correlation between the rate of metabolism of a sulfonamide and the extent of protein binding. 

Some disease states (e.g., hyperalbuminemia, hy-poalbuminemia, uremia, hyperbilirubinemia) have been associated with changes in plasma protein binding of drugs. For example, in uremic patients the plasma protein binding of certain acidic drugs (e.g., penicillin, sulfonamides, salicylates, and barbiturates) is reduced. 

Methotrexate clearance can be decreased by the coadministration of NSAIDs however, this not usually a problem with the low doses of methotrexate used to treat arthritis. Methotrexate can be displaced from plasma protein binding sites by phenylbutazone, pheny-toin, sulfonylureas, and sulfonamides and certain other antibiotics. The antifolate effects of methotrexate are additive with those of other folate-inhibitory drugs, such as trimethoprim. 

Acetylation of sulfonamides is reduced by protein binding, but the formation of glucuronide conjugates is unaffected. 

Sulfonamides can be divided into three major groups (1) oral, absorbable (2) oral, nonabsorbable and (3) topical. The oral, absorbable sulfonamides can be classified as short-, intermediate-, or long-acting on the basis of their half-lives (Table 46-1). They are absorbed from the stomach and small intestine and distributed widely to tissues and body fluids (including the central nervous system and cerebrospinal fluid), placenta, and fetus. Protein binding varies from 20% to over 90%. Therapeutic concentrations are in the range of 40-100 mcg/mL of blood. Blood levels generally peak 2-6 hours after oral administration. 

In addition, the solubilized sulfonamides as a group diffuse very widely into the tissues, penetrating into all fluids, including urine, bile, and milk. The degree of tissue penetration is influenced by several factors, including the ionization state and lipophilicity of the particular sulfonamide, the vascularity of the absorption site, and the degree of protein binding. 

The serum-protein binding ability, which varies between animals and is also influenced by the disease state of the animal, will also determine the free diffusible concentration. This, in turn, will have an effect on the elimination of drug residues as well as on their penetration in eggs or milk. This effect will be more pronounced for drugs with a higher tendency for protein binding such as sulfonamides, doxycycline, and cloxacillin (47). 

Hypoglycemia, often during the first hours of combining the two drugs, is the result of an important interaction between sulfonylureas and sulfonamides (184—187). For example, the half-life of tolbutamide was increased from 9.5 to 29 hours by chronic sulfaphenazole and from 9.2 to 26 hours by a single dose of sulfaphenazole (188). Interference by sulfonamides with the protein binding of sulfonylureas may contribute. 

Sulfonamides [NE] Inhibit warfarin metabolism displace protein binding. 

Inconclusive evidence suggests that salicylic acid can potentiate valproate toxicity (mechanism unclear). Sulfafurazole, sulfamethoxypyridazine, possibly other sulfonamides, and sulfinpyrazone displace phenytoin from plasma protein binding sites with different affinities total phenytoin concentrations may underestimate the concentration of unbound (pharmacologically active) drug. 

The ability of zinc in carbonic anhydrase to become five-coordinate is also confirmed by the structural studies on enzyme-inhibitor complexes discussed in Section 62.1.4.2.1. There is much evidence for the coordination of anionic inhibitors to the metal, while the competitive inhibitor imidazole gives a five-coordinate centre. Sulfonamides are powerful inhibitors which bind directly to the zinc and also interact with the protein. The sulfonamide acetazolamide has significant affinity for the apoenzyme. It is probable " that the first interaction between the enzyme and aromatic sulfonamides is a hydrophobic interaction between the aromatic ring and residues in the active site cavity, followed by ionization of the SO2NH2 group prior to complex formation. Sulfonamides only bind to the zinc and cobalt enzymes, i.e. the two metals that give an active enzyme. 

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