Sulfonamides and Diaminopyrimidines

1 for sulfadoxine), at physiological pHs of most body fluids they are mainly un-ionized. The un-ionized moiety is generally lipid-soluble, but this varies (lipophilicity high for sulfisoxazole, low for sulfaguanidine) between drugs. The consequence is that sulfonamides generally readily cross 

Diaminopyrimidines are lipid-soluble weak organic bases, partially ionized at physiological pH, which, in contrast to sulfonamides, penetrate readily into cells and are poorly reabsorbed from acid urines. 

PHARMACOKINETICS, DISTRIBUTION, BIOAVAILABILITY, AND RELATIONSHIP TO ANTIBIOTIC RESIDUES 

An influence of disease on the absorption of sulfaquinox-aline was established by Williams et al., who reported a 

5-fold greater bioavailability in chickens infected with Escherichia acervalina and E. tenella in comparison with uninfected birds. 

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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... 

Readily cross cell membranes generally moderate to good absorption from GIT but species-dependent effective concentrations achieved in intra- and transcellular as well as extracellular fluids except for poor penetration of sulfonamides into intracellular fluid due to acidic environment ability to penetrate into CSF and ocular fluids depends on plasma protein binding (e.g., most sulfonamides and diaminopyrimidines penetrate well) weak acids are ion-trapped in fluids alkaline relative to plasma, such as herbivore urine weak bases are ion-trapped in fluids acidic relative to plasma (e.g., prostatic fluid, milk, intracellular fluid, carnivore urine) commonly dependent on biotransformation for termination of activity but may also be excreted unchanged in urine and/or bile some drugs actively secreted into bile... 

As was already stated, biguanides and diaminopyrimidines are active against exoerythrocyte and erythrocyte forms for plasmodia. Each of these dmgs can be used individually for prevention however, the maximal effect is achieved when used in combination with sulfonamides. 

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. 

Diaminopyrimidines are weak bases. Peak plasma concentrations are reached early and diaminopyrimidines are soon found in high concentrations in tissues. In fact, the tissue concentrations are often higher than the concentrations in serum. When inflammation is present, trimethoprim levels in the CSF may reach 50% of the plasma concentrations. CSF concentrations of pyrimethamine are 25-50% of the plasma concentrations. The Vd for trimethoprim and pyrimethamine is 1.51/kg in horses. The protein binding of trimethoprim is moderate (50%). There is no protein-binding interaction between the sulfonamides and the diaminopyrimidines. 

Endoh, Y.S. Takahashi, Y. Nishikawa, M. HPLC determination of sulfonamides, their N4-acetyl metabolites and diaminopyrimidine coccidiostats in chicken tissues. J.Liq.Chromatogr., 1992, 15, 2091-2110 [skin plasma muscle liver kidney LOD 20-50 ng/gK also N-acetyldiaveridine, N-ace-tylsulfadiazine, N-acetylsulfadimethoxine, N-acetylsulfamethoxazole, N-acetylsulfamonomethoxine, N-acetylsulfaquinoxaline, diaveridine, ormetoprim, sulfadiazine, sulfadimethoxine, sulfamonome-thoxine, sulfaquinoxaline, trimethoprim]... 

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. 

Table 1.14 lists the properties of sulfonamides and antibacterial diaminopyrimidines. 

Outstanding among drugs which inhibit the production of DNA from several stages back in the biosynthetic pathway are the sulfonamides and the 2,4-diaminopyrimidines used as antibacterials and anti-malarials. All of the chemotherapeutic sulfonamides, whether simple sulfanilamide 4.6a) or its more complex heterocyclic derivatives 4.6b) including sulfadiazine, competitively inhibit the enzyme dihydrofolate synthetase which produces dihydrofolic acid 2.14) (see p. 31). The basis of this inhibition, as outlined in Section 2.1 (p. 31), is the similarity in the steric and electronic properties of/ -aminobenzoic acid 2.12) (which the enzyme is ready to build into new molecules of dihydrofolic acid) and the sulfonamides 4.6) which, when taken up by the enzyme, merely block it. The basis of the selectivity of these antibacterial sulfonamides depends on two factors, which reinforce one another (i) mammals lack the enzymes necessary for the synthesis of dihydrofolic acid, and hence they tolerate these sulfonamides very well (ii) pathogenic bacteria lack the permease... 

VI.a.2.4. Diaminopyrimidines. Pyrimethamine is a dihydrofolate reductase inhibitor, like the biguanides, and is structurally related to trimethoprim. It is seldom used alone. Pyrimethamine in fixed combinations with dapsone or sulfadoxine is used for treatment and prophylaxis of chloroquine-resistant falciparum malaria. The synergistic activities of pyrimethamine and sulfonamides are similar to those of trimethoprim/sulfonamide combinations. Resistant strains of Plasmodium falciparum have appeared world wide. Prophylaxis against falciparum... 

Baquiloprim is a diaminopyrimidine derivative acting synergistically with sulfonamides (221). In cattle, it is used orally, intravenously, or intramuscularly for treatment of mastitis and infections of the respiratory and gastrointestinal tract, whereas, in swine, it is administered intramuscularly for treatment of the mastitis-metritis-agalactia syndrome and infections of the respiratory and gastrointestinal tract. 

Sulfonamides maintain a significant role even today, because they are often used in combination with other antibacterials. For example, trimethyoprim, 35, has a diaminopyrimidine structure that has proved to be a highly selective, orally active, antibacterial, and antimalarial agent [6]. Trimethyoprim is combined to sulfamethoxazole, 36, for the treatment of bacterial respiratory tract infections and gastrointestinal infections [9]. 

Pyrimethamine is the most active antimalarial of the 2-4-diaminopyrimidines, its effect being due to inhibition of the conversion of foUc acid to its active form, folinic acid. It is also effective in toxoplasmosis. Its antiprotozoal and antimalarial activity is enhanced by the addition of 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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