Sulfonamides glucuronides

Recently the hydroxy metabolites of various sulfonamides could be Isolated and purified, so that specific HPLC techniques could be developed (22,23). As shown in Figure 1, sulfadimidine can be metabolized by hydroxylation at the 5 and 6 position of the pyrimidine ring and by the acetylation- deacetylation pathway (21). After hydroxylation, the metabolites may become glucuronidated and also acetylated (Figure 2). The hydroxy metabolites are microbiologically active and they can be potentiated by trimethoprim (13). 

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

Glucuronidation UDP glucuronic acid UDP glucuronosyltransferase (microsomes) Phenols, alcohols, carboxylic acids, hydroxylamines, sulfonamides Nitrophenol, morphine, acetaminophen, diazepam, N-hydroxydapsone, sulfathiazole, meprobamate, digitoxin, digoxin... 

A portion of absorbed drug is acetylated or glucuronidated in the liver. Sulfonamides and inactive metabolites are then excreted into the urine, mainly by glomerular filtration. In significant renal failure, the dosage of sulfonamide must be reduced. 

Figure 13.21. Major glucuronidation reactions involving phenols, alcohols, carboxylic acids, car-bamic acids, hydroxylamines and hydroxylamides, carboxamides, sulfonamides, various amines, thiols, dithiocarboxylic acids, and 1,3-dicarbonyl compounds.

However, it proved to be inactive as a diuretic when administered orally to dogs. Later it was shown that the compound was rapidly metabolized to the 2-mercaptobenzothiazole, which was excreted as the glucuronide conjugate (9). More recently, the 6-ethoxybenzothiazole-2-sulfonamide (ethoxzol-amide), has been found to be active in animals and effective in man (26). 

Orally active, metabolized by the liver mainly via glucuronidation—drugs that interfere and may increase ZDV toxicity include acetaminophen, ASA, cimeti-dine, probenecid, and sulfonamides. 

Drug interactions Drugs that undergo hepatic glucuronidation, including acetaminophen, benzodiazepines, cimetidine, and sulfonamides, may increase plasma levels of zidovudine. Metabolism of zidovudine may also be inhibited by azole antifungals and by protease inhibitors. Rifampin increases the clearance of zidovudine. 

The orally administered sulfonamides are well absorbed from the gastrointestinal (Gl) tract, distributed fairly widely, and excreted by the kidney. The drugs are bound to plasma protein (sulfisoxazole, 30-70%, sulfamethoxazole, 70%) and, as such, may displace other protein-bound drugs as well as bilirubin. The latter phenomenon disqualifies them for use in late term pregnancy as they can cause neonatal jaundice. Sulfonamides are partly deactivated by acetylation at N-4 and glucuronidation of the anilino nitrogen in the liver. 

Glucuronidation UDP-glucuronic acid UDPG-transferase (microsomes) Phenols alcohols carboxylic acids primary amines hydroxylamines sulfonamides, etc. 

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