Sulfonamides and Diaminopyrimidine Potentiators

They are still widely used as feed additives for treatment or prevention of coccidiosis. In ruminants, sulfaquinoxaline, sulfadimethoxine, and sulfame-thoxypyridazine are the most useful coccidiostats, although sulfachlorpyrazine, sulfathiazole, and sulfamonomethoxine are also highly effective. Additional coccidiostats or adjuvants such as amprolium, chlortetracycline, and ethopabate are often combined with sulfonamides for synergistic effects in poultry. 

Except for sulfonamides such as phthalylsulfathiazole and succinylsulfathi-azole, which are not absorbed from the intestine, most members of the sulfonamide group follow a common pharmacological pattern. Following oral administration, absorption rates of sulfonamides are approximately proportional to their water solubility although these can vary between species. Thus, pigs and horses absorb sulfonamides move slowly than birds but better than cattle. Exceptions are sulfapyridine, which is slowly absorbed in most species, and sulfamethazine, which is second to sulfanilamide in the rate of absorption. 

The absorption of sulfonamides by diseased animals may be quite different from that observed in healthy individuals of the same species. Experimental rumen stasis, produced by atropine, markedly reduced the absorption of sulfamethazine following its oral administration to sheep. 

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 extent to which a sulfonamide is acetylated depends upon the drug administered and the animal species. Acetylsulfathiazole is the principal metabolite found in the urine of cattle, sheep, and swine after enteral or parenteral administration of sulfathiazole. However, sheep can acetylate only 10% of the dose, while cattle can acetylate 32%, and swine 39%. When sulfamethazine was administered intravenously or orally to cattle, the animals eliminated 11% or 25% of the dose, respectively, in urine as N -acetylsulfamethazine. The increased acetylation that occurred following tlie oral administration may be related to the increased exposure of sulfamethazine to liver enzymes following its absorption into the portal circulation. The acetylation rate may also be affected by the health status of an animal. Tims, cows suffering from ketosis in cows acetylate sulfonamides at much lower extent. 

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Fig. 3.7 Chemical structures of commonly used sulfonamides and diaminopyrimidine potentiators.

Extraction of sulfonamides and diaminopyrimidine potentiators from edible animal products should render the bound residues soluble, remove most or all of the proteins, and provide high yields for all analytes. Sample extraction/deprotei-nization is traditionally accomplished with polar solvents including acidic aqueous solutions (211,214-222), acetonitrile (56,223-232), chloroform (233-240), ethyl acetate (29,241-244), dichloromethane (204,242,245-247), acetone (194, 248, 249), or various combinations of them. Use of dichloromethane at pH 10 in the presence of an ion-pairing reagent (tetrabutylammonium) has also been reported to work extremely well in the extraction of sulfadimethoxine and ormeto-prim residues from catfish muscle (250) and animal tissues (251). Anhydrous sodium sulfate may be added to dehydrate tissue samples to permit better exposure of the matrix to tire solvent. 

Liquid-liquid partitioning has been used for many years for Ure purification of sulfonamides and diaminopyrimidine potentiators. When partitioning from an organic into an aqueous phase, the adjustment of the pH of Ure aqueous phase is critical to obtain quantitative recoveries.. Sulfonamides are generally extracted from Ure primary organic sample extract into strong acidic (238, 239, 242, 249, 252-254) or basic (241, 248, 255) aqueous solutions. For better sample cleanup, back-extraction of Ure analyte(s) into dichloromethane (241, 253, 254), or ethyl acetate (256), after pH adjustment of the aqueous phase at values between 5.1... 

Following their extraction and cleanup, residues of sulfonamides and diaminopyrimidine potentiators in sample extracts can be detected by direct nonchro-matographic methods, or thin-layer, gas, liquid, or supercritical fluid chromatographic methods (Table 29.7). 

Physicochemical Methods for Sulfonamides and Diaminopyrimidine Potentiators in Edible Animal... 

The sulfonamides are a group of organic compounds with chemotherapeutic activity they are antimicrobial agents and not antibiotics. They have a common chemical nucleus that is closely related to PABA, an essential component in the folic acid pathway of nucleic acid synthesis. The sulfonamides are synergistic with the diaminopyrim-idines, which inhibit an essential step further along the folate pathway. The combination of a sulfonamide and a diaminopyrimidine is advantageous because it is relatively non-toxic to mammalian cells (less sulfonamide is administered) and is less likely to select for resistant bacteria. Only these so-called potentiated sulfonamides are used in equine medicine. These drugs are formulated in a ratio of one part diaminopyrimidine to five parts sulfonamide, but the optimal antimicrobial ratio at the tissue level is 1 20, which is achieved because the diaminopyrimidines are excreted more rapidly than the sulfonamides. 

The sulfonamide class contains a large number of antibacterial drugs, including sulfadiazine, sulfamethazine (sulfadimidine), sulfathiazole, sulfamethoxazole, and many more. Potentiated sulfonamides, in which a sulfonamide and an antibacterial diaminopyrimidine such as trimethoprim are combined, demonstrate improved efficacy compared with sulfonamides alone. Relatively few sulfonamides are currently (as of 2011) approved for use in food-producing species. This is attributed to numerous factors, including toxicological concerns associated with some sulfonamides and the lack of contemporary data to support the historical uses of other sulfonamides. 

Resistance to the diaminopyrimidines usually occurs by plasmid-encoded production of diaminopyrimidine-resistant DHFR. Excessive bacterial production of DHFR and a reduction in the ability of the drug to penetrate the bacterial cell wall also results in resistance. There is less resistance to the potentiated sulfonamides than to the individual agents. 

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