Sulphonamides metabolism

Drug-metabolizing enzymes also appear in full range in the liver during early childhood, and some drugs seem to be metabolically cleared more rapidly at this time - e.g., sulphonamides metabolized by acetylation. However, some of the conclusions about drug clearance rates in children have been made only on the basis of altered plasma Ti/2 for the drug. 

Folate metabolism Sulphonamides (also ) Trimethoprim Pyrimethamine Trimetrexate / Inhibit folate synthesis Inhibits dihydrofolate reductase Inhibits dihydrofolate reductase Inhibits dihydrofolate reductase Not present in mammalian cells Mammalian enzyme not inhibited Mammalian enzyme not inhibited Toxicity overcome with leucovorin... 

Sulphonamides are structural analogues of PABA. They competitively inhibit the incorporation of PABA into dihydropteroic acid and there is some evidence for their incorporation into false folate analogues which inhibit subsequent metabolism. The presence of excess PABA will reverse the inhibitory action of sulphonamides, as will thymine, adenine, guanine and methionine. However, these nutrients are not normally available at the site of infections for which the sulphonamides are used. 

Investigation of a related indole template, however, yielded potent compounds, as exemplified by the sulphonamide derivative (33). Activity was improved further by introducing steric constraints to the sidechain and introduction of a 7-methyl substituent on the indole ring, leading to compound (34) [82]. Derivatives generally possessed only moderate pharmacokinetic properties however (clearance 25-45 ml/min/kg in dog), which was attributed to metabolic vulnerability of the indole (C2-C3) double bond. Attempts to block metabolism by C2, C3 di-methyl substitution resulted in the loss of oxytocin activity. 

Enzymatic-metabolic activation (in part unknown)/phenobarbital-like promotion Hepatic enzyme induction, thyroid enzyme inhibition/axazepam, amobarbital, sulphonamides, thioureas Gastric secretory suppression, gastric atrophy induction (climetidine, omeprazole, butachlor... 

Absence of an enzyme or metabolic pathway Applies to some antibiotics and certain bacterial species, e.g. folate auxotrophs, trimethoprim and sulphonamides... 

Alteration of a metabolic pathway, for example some sulphonamide-resistant bacteria switch to using pre-formed fohc acid, rather than synthesise the precursor para-aminobenzoic acid (PABA), which is the reaction inhibited by sulphonamides. 

PHENYTOIN CHLORAMPHENICOL, CLARITHROMYCIN, ISONI-AZID, METRONIDAZOLE, SULPHONAMIDES, TRIMETHOPRIM t phenytoin levels Inhibited metabolism Monitor phenytoin levels... 

ANTICOAGULANTS-ORAL METRONIDAZOLE, SULPHONAMIDES, TRIMETHOPRIM t anticoagulant effect Inhibition of CYP2C9-mediated metabolism of oral anticoagulants Monitor INR every 2-3 days... 

Acetylation is an important metabolic route for aromatic and heterocyclic amines, hydrazines and sulphonamides. An amide bond is formed between the amino group of the chemical and the acetate. This reaction is catalyzed by acetylases, the acetyl group being donated by acetyl CoA. 

The enzyme dihydrofolic acid (DHF) S5mthase (see below) converts p-aminobenzoic acid (PABA) to DHF which is subsequently converted to tetrahydric folic acid (THF), purines and DNA. The sulphonamides are structurally similar to PABA, successfully compete with it for DHF s)mthase and thus ultimately impair DNA formation. Most bacteria do not use preformed folate, but humans derive DHF from dietary folate which protects their cells from the metabolic effect of sulphonamides. Trimethoprim acts at the subsequent step by inhibiting DHF reductase, which converts DHF to THF. The drug is relatively safe because bacterial DHF reductase is much more sensitive to trimethoprim than is the human form of the enzyme. Both sulphonamides and trimethoprim are bacteriostatic. 

Pharmacokinetics. Sulphonamides for systemic use are absorbed rapidly from the gut. The principal metabolic path is acetylation and the capacity... 

Antimicrobials. Aztreonam, cefamandole, chloramphenicol, ciprofloxacin, co-trimoxazole, erythromycin, fluconazole, itraconazole, ketoconazole, metronidazole, miconazole, ofloxacin and sulphonamides (including co-trimoxazole) increase anticoagulant effect by mechanisms that include interference with warfarin or vitamin K metabolism. Rifampicin and griseofulvin accelerate warfarin metabolism (enzyme induction) and reduce its effect. Intensive broad-spectrum antimicrobials, e.g. eradication regimens for Helicobacter pylori (see p. 630), may increase sensitivity to warfarin by reducing the intestinal flora that produce vitamin K. 

The chemical nature and related physicochemical properties largely govern the distribution and elimination, which refers to biotransformation (metabolism) and excretion, of antimicrobial agents. The majority of antimicrobial agents are weak organic electrolytes, either weak acids (penicillins, cephalosporins, sulphonamides) or weak bases (aminoglycosides, lincosamides, macrolides, diaminopyrimidines, metronidazole), while fluoroquinolones, tetracyclines and rifampin are amphoteric compounds, and chloramphenicol and its... 

Acetylation is an important route of metabolism for aromatic amines, sulphonamides, hydrazines and hydrazides and there is a wide variety of substrates. This metabolic reaction is one of two types of acylation reaction and involves an activated conjugating agent, acetyl CoA. It is hence a type 1 reaction. Acetylation is notable in that the product may be less water soluble than the parent compound. This fact gave rise to problems with sulphonamides when these were administered in high doses. The acetylated metabolites, being less soluble in urine, crystallized out in the kidney tubules, causing tubular necrosis (table 4,1). The enzymes which catalyse the acetylation reaction, acetyltransferases, are cytosolic and are found in the liver, in both hepatocytes and Kupffer cells, in the gastrointestinal mucosa and in white blood cells. The enzyme has been purified and its mechanism of action extensively studied and is now well understood. This involves first acetylation of the enzyme by acetyl CoA... 

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