Sulfanilamide metabolism

Some related antibacteiials are also included with the sulfonamides. The azo dye, Piontosil (3) is metabolized to sulfanilamide in and was the piogenitoi of the sulfa dmgs. Also, the antibacteiial sulfones, eg, dapsone (4), are believed to act in a similai fashion on enzymes involved with synthesis of fohc acid, leading to bacterial growth inhibition. 

Careful metabolic work on this drug by a group of French workers showed that the agent was in fact cleaved to sulfanilamide (83) and the amine, 84, in vivo. Testing of the two fragments revealed that the activity of the drug resided entirely in the sulfanilamide fragment. That compound in fact showed full activity when administered alone in vitro or in vivo. ... 

Dihydropteroic acid (85) is an intermediate to the formation of the folic acid necessary for intermediary metabolism in both bacteria and man. In bacteria this intermediate is produced by enzymatic condensation of the pteridine, 86, with para-amino-benzoic acid (87). It has been shown convincingly that sulfanilamide and its various derivatives act as a false substrate in place of the enzymatic reaction that is, the sulfonamide blocks the reaction by occupying the site intended for the benzoic acid. The lack of folic acid then results in the death of the microorganism. Mammals, on the other hand, cannot synthesize folic acid instead, this compound must be ingested preformed in the form of a vitamin. Inhibition of the reaction to form folic acid Ls thus without effect on these higher organisms. 

Possibly the most significant discovery in the metabolism of aromatic azo compounds had implications that heralded the age of modem chemotherapy. It was shown that the bactericidal effect of the azo dye Prontosil in vivo was in fact due to the action of its transformation product, sulfanilamide, which is an antagonist of 4-aminobenzoate that is required for the synthesis of the vitamin folic acid. Indeed, this reduction is the typical reaction involved in the first stage of the biodegradation of aromatic azo compounds. 

The formation of sulfa drugs is another excimple of a multistep synthesis. The sulfa drugs cire bactericides, effective c ainst a wide variety of bacteria because they mimic p-aminobenzoic acid (Figure 13-48). Many bacteria require p-aminobenzoic acid, which they cire unable to synthesize, and need to synthesize folic acid. Many types of sulfa drugs exist, and most of them involve the substitution of one of the hydrogen atoms on the -SO2-NH2. Prontosil (Figure 13-49) was the first commercially available sulfa drug. The metabolism of prontosil produced sulfanilamide. 

A correlation may be established between the concentration of oxidized lipids and the TEARS value, expressed as MDA equivalents, in uM units. Correction is due in some cases for the interference by dyes or other factors. For example, the presence of anthocyanins in red cabbage leaves or turbiditjf causes overestimation of lipid hydroperoxides in plant tissue by the TEARS method. TEARS was used to assert the level of endogenous peroxides in hypo- and hyperthyroidism, both conditions being characterized by low lipid and lipoprotein plasma levels and enhanced oxidative metabolism . In a procedure for determination of TEARS in edible oils, the sample is placed in a centrifuge at 12000 g before measuring at 532 nm (e = 1.56 x 10 M cm ) . A usual procedure for determination of TEARS in certain complex matrices involves steam distillation of the aldehydes responsible for the value, instead of extraction. In nitrite-cured meats, excess nitrite may cause nitrosation of MDA, thus interfering with distillation. To avoid this interference sulfanilamide is added, which is converted to a diazonium salt and... 

Species differences in the metabolism of drug may be due to the difference in the rate of metabolism or in their metabolites difference. Certain drugs have been found safe and non-toxic in animals, but when they were tested in human beings severe toxic effects were observed. For example, when sulfanilamide was tested in dog it was found safe and non-toxic, but when it was administered to human being, certain toxic effects like the hematuria, renal failure were observed. 

The compound sulfanilamide exhibits a structural similarity to para-amino benzoic acid (PABA). Woods and Fields proposed the theory that sulfonamides, being structurally similar to PABA, inhibit bacterial folate synthetase so that folic acid is not formed which is needed for a number of metabolic reactions. Folic acid derived from PABA is essential for bacterial metabolism. Sulfonamides inhibit the enzyme folic acid synthetase which is... 

In the body all sulfa drugs are metabolized to sulfanilamide, which binds to the bacterial enzymes and keeps them from doing their job. 

In 1940 sulfanilamide was shown to inhibit carbonic anhydrase. It was not useful as a diuretic because the doses required to produce diuresis were excessive. Investigation of some heterocyclic sulfonamides produced some clinically effective diuretics, for example ethoxzolamide (188), but the first really useful sulfonamide diuretic was acetazolamide (189). This compound also has anticonvulsant activity which is probably related to the presence of carbonic anhydrase in the CNS. Acetazolamide had the disadvantage of producing a metabolic acidosis through the excretion of HCO3- rather than Cl and it was found that some 1,3-disulfonamidobenzenes gave a more balanced diuresis. 

E.g., prontosil (Figure 1.12) is entirely inactive on bacterial cultures. Only after its reductive cleavage in human metabolism the active metabolite sulfanilamide is released, and antibacterial activity becomes manifest. 

For the logarithmic value of kAc, Equation 13 and its modification, Equation 14, were formulated, where KA° is the dissociation constant of sulfanilamide, a, p c p, and c are constants, and [H+] is the hydrogen ion concentration in the blood. We used Equation 14 to analyze the acetylation data. The second term on the left of Equation 14 expresses the dissociation effect of the free drug, but it does not mean that the neutral form is only responsible for metabolism. 

Prontosil and other sulfur-containing antibiotics are collectively called sulfa drugs. Prontosil is not the active agent itself. In cells, it is metabolized to sulfanilamide, the active drug. To under-... 

In 1935, a red dye called Prontosil, 30, was discovered to have antibacterial properties in vivo (i.e., when given to laboratory animals). No antibacterial effect was observed in vitro (i.e., Prontosil could not kill bacteria grown in a test tube). This result remained a mystery until it was discovered that Prontosil was not in fact the antibacterial agent. Instead, it was found that the Prontosil was metabolized by bacteria present in the small intestine of the test animal, and broken down to sulfanilamide 31 [6]. 

Sulfanilamide is an effective antibiotic and has been used safely for many years to treat streptococcal and pneumococcal infections. However, sulfanilamide is generated from the azo-reduction of Prontesil, which is an example of a prodrug. A prodrug has no therapeutic effect on its own but generates active metabolites. The metabolism of prontesil, a prodrug, to its active metabolite, sulfanilamide, can be used as an example of azo reduction (Figure 6). 

The metabolism of a number of sulfonamides, such as sulfanilamide. sulfamethoxazole (Gantanol). sulfisoxa-zx>le (Gantrisin). sulfapyridine (major metabolite from azo reduction of sulfasalazine. Azulfidine), and sulfamethazine. " " occurs mainly by acetylation at the N-4 position. With sulfanilamide, acetylation also takes place at the sul-... 

Investigations into drugs suspected of causing cancer in humans have included aryl amine derivatives such as Paracetamol (17a)61 and phenacetin (17b). Metabolism of acetanilide (17c) yields aniline, and of 17b A-hydroxyphenacetin (18)62, in accord with views on mechanisms of toxicity as discussed in the next section. Tumor formation was induced in rats at excessively high dose levels and only under certain conditions. Drugs found to cause methemoglobinemia include antipyrine, acetanilide, sulfanilamide, sul-fapyridine, sulfathiazole, sulfonal and thional. 

Here too, species differences are reported, but this parameter is accessible to in vitro studies. Both protein-binding and passive reabsorption, factors that determine the rate of renal excretion, are related to the partition coefficients of the compounds119,12°. The half-life of various non- or poorly metabolized sulfanilamides is strongly dependent on the partition coefficient, as can be seen from Fig. 13121. ... 

Fig. 13. Physicochemical characteristics of sulfanilamides in relation to half-life. After Stroller121 - Only slowly metabolized sulfanilamides are incorporated...

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