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Sulfonamides are a group of synthetic organic compounds that have played an important role as effective chemotherapeutics in bacterial and protozoal infec-tions in veterinary medicine. Phthalylsulfathiazole, succinylsulfathiazole, sulfa-bromomethazine, sulfachlorpyrazine, sulfachlorpyridazine, sulfadiazine, sulfadi-methoxine, sulfamethazine (sulfadimidine), sulfadoxine, sulfaethoxypyridazine, sulfaguanidine, sulfamerazine, sulfamethoxazole, sulfamethoxydiazine, sulfame-thoxypyridazine, sulfamonomethoxine, sulfapyridine, sulfaquinoxaline, sulfathia-zole and sulfisoxasulfathia-zole have all been used in food-producing animals (Fig. 3.7).

They share a common chemical nucleus that is essential for the exhibited antibac-terial activity and comes from sulfanilamide, the simpler member of the sulfon-amide group; in this nucleus, the sulfonsulfon-amide (-SO2NH2-) nitrogen has been designated as N¹, and the amino (-NH2) nitrogen as N⁴. Most sulfonamides have been synthesized by chemical substitution at the N¹ position since substitution at the N⁴ position results, with certain exceptions, in compounds with greatly reduced antibacterial activity compared to their unsubstituted counterparts.

Parent sulfonamides are relatively insoluble in water but their sodium salts have greater water solubility than the parents compounds and are commonly included in commercial preparations. Indications for sulfonamides are wide owing to their wide spectrum of activity. They cover infectious diseases of the digestive and respiratory tracts, secondary infections, mastitis, metritis, and foot rot. Sulfon-amides are administered to animals by all known routes at dosages noticeably higher than those for antibiotics. Sometimes several sulfonamides may be com-bined in only one preparation to ensure a wider range of activity and to reduce toxicity. Some sulfonamides are also used to treat bacterial infections in horses, cattle, sheep, goats, pigs, poultry, and fish in the form of potentiated formulations with synthetic diaminopyrimidines such as trimethoprim, ormetoprim, or baquilo-prim. Trimethoprim is usually combined with sulfadiazine or sulfadoxine, whereas ormetoprim is combined with sulfadimethoxine, and baquiloprim with sulfamethazine. These formulations are believed to act synergistically on specific targets on bacterial DNA synthesis, with the sulfonamide blocking the conversion of p-aminobenzoic acid to dihydrofolic acid and the diaminopyrimidine inhibiting the conversion of dihydrofolic acid to tetrahydrofolic acid in the folic acid path-way, thus potentiating the antibacterial effects of the sulfonamide.

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 coc-cidiostats or adjuvants such as amprolium, chlortetracycline, and ethopabate are often combined with sulfonamides for synergistic effects in poultry.

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FIG. 3.7 Continued

Except for sulfonamides such as phthalylsulfathiazole and succinylsulfathi-azole, which are not absorbed from the intestine, most members of the sulfon-amide group follow a common pharmacological pattern. Following oral adminis-tration, 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 ioniza-tion state and lipophilicity of the particular sulfonamide, the vascularity of the absorption site, and the degree of protein binding.

Metabolism of sulfonamides proceeds with acetylation, oxidation, conjuga-tion with sulfate or glucuronic acid, and cleavage at varying degrees of their heterocyclic rings. The metabolism of sulfonamides is important because it affects the antibacterial activity and toxicity of the compounds. In general, the acetylated, hydroxylated, and conjugated forms of the sulfonamides exhibit a marked de-crease in antibacterial activity compared to the parent compounds. The acetylated forms of all sulfonamides except those of sulfadiazine, sulfamerazine, and sulfa-methazine are less water-soluble than the parent compounds and thus are more likely to precipitate in the urine causing renal damage. In contrast, the hydroxy-lated and conjugated metabolites are more soluble than the parent sulfonamides, and therefore are less likely to damage renal tissues.

The extent to which a sulfonamide is acetylated depends upon the drug administered and the animal species. Acetylsulfathiazole is the principal metabo-lite 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 N⁴-acetylsulfamethazine. The increased acetylation that occurred following the 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. Thus, cows suffering from ketosis in cows acetylate sulfon-amides at much lower extent.

Oxidation of sulfonamide rings is another important metabolic process in certain species. Sheep eliminate 25% of an intravenous dose of sulfamethazine in

the form of 4-hydroxymethyl-6-methyl-2-sulfanilamidopyrimidine, while cattle eliminate only 12% of the dose. In contrast, swine are unable to hydroxylate this drug since hydroxylated metabolites cannot not be found in urine after oral or intravenous administration of the compound. In addition, sulfonamides and their metabolites are often found in the urine in conjugated forms with glucuronic or sulfate acid, the amount of conjugation being dependent upon the individual drug and the animal species to which this is given. Conjugation commonly occurs at the N¹, N², or hydroxylation sites of the compounds. Ring cleavage, which also sometimes occurs, appears to be a minor metabolic pathway since only small amounts of degradation products are excreted in the urine.

Following their metabolic transformation, sulfonamides are eliminated in urine, feces, bile, and milk. However, the kidney is the organ primarily involved in the excretion of these drugs. Sulfonamide residues deplete from body tissues and fluids with widely variable velocity that depends on many factors including the nature of the compound, its formulation and the route of administration, and the animal species. Nevertheless, sulfonamide residues eliminate much earlier from liver, kidney, and milk than from muscle and fat. Withdrawal periods in meat and milk differ, therefore, for each sulfonamide.

Sulfadiazine is a relatively short-acting sulfonamide with an elimination half-life of about 3 h in cattle. The importance of this drug for control of furuncu-loses in fish is determined by its combined use with the potentiator trimethoprim.

When a single dose of radiolabeled sulfadiazine was administered to eels at 7 C (200), highest initial radioactivity was observed in blood, liver, kidney, and skin, with a tendency for accumulation in bile and skin. In another pharmaco-kinetic study (201) on sea-water rainbow trout fed a combination of sulfadia-zine–trimethoprim, the elimination process for both sulfadiazine and trimetho-prim rapidly reached a point at which only a small but persistent residue was left; at 8 C as opposed to 10 C, sulfadiazine was the more potent residue promoter, still being detected at 90 days posttreatment. This was suggested to be a result of the greater binding ability of sulfadiazine as a weak electrolyte. The authors proposed a withdrawal period for sulfadiazine–trimethoprim of 60 days at water temperatures above 10 C for tabled-size fish, and a prohibition on its use below 10 C for such fish.

Another study (202) of sulfadiazine pharmacokinetics in carp treated by the intraperitoneal route showed an elimination half-life of 17.5 h at 20 C. Both acetylation and hydroxylation metabolic pathways appeared to occur, but they only represented 2% and 0.41% of the dose, respectively. This is in strong contrast to the metabolism profile of sulfadiazine in mammals, where hydroxylation is much more important.

When sulfadiazine in addition with trimethoprim was fed to pigs, the ab-sorption of trimethoprim from the gastrointestinal tract was faster than the absorp-tion of sulfadiazine, whereas the eliminaabsorp-tion of trimethoprim was slower than

that of sulfadiazine (203). One day after the last multiple-dose administration, the maximum tissue concentration of trimethoprim was 0.29 ppb and detected in liver, while the maximum tissue concentration of sulfadiazine was 0.23 ppb and detected in kidneys. Neither drug could be detected in any tissue at day 8 posttreat-ment.

Sulfamethazine (sulfadimidine) is perhaps one of the most widely used sulfonamides. It is employed largely in mass medication of pigs to control atrophic rhinitis and other infections, although it is also used in other species such as cattle. Beyond its therapeutic applications, sulfamethazine is widely used to pro-mote growth in food-producing animals, although it is not approved for use in lactating dairy cows. This drug has been shown to be a thyroid nongenotoxic carcinogen in rodents.

Pharmacokinetic studies indicate that sulfamethazine is rapidly absorbed and excreted in farm animal species. The elimination is generally more rapid when the drug is injected than when it is administered orally with the feed or drinking water.

Sulfamethazine is metabolized by hydroxylation at the 5 and 6 positions of the pyrimidine ring and by acetylation–deacetylation pathways. After hydrox-ylation, the metabolites may become glucuronidated and also acetylated (204).

In cows and calves (205), sulfamethazine is extensively metabolized into hydroxyl derivatives and, to a lesser extent, acetylated into N⁴-acetylsulfamethazine. Hy-droxylation of the 6-methyl group to form 6-hydroxymethylsulfamethazine domi-nates hydroxylation at the 5 position.

Sulfamethazine concentrations in plasma exceed those in muscle, kidney, or liver tissue, but run parallel to those in milk. The N⁴-acetylsulfamethazine concentrations in muscle, kidney, and liver are always below those of the parent compound. In contrast, the 6-hydroxymethylsulfamethazine concentration in the kidney exceeds that of sulfamethazine.

Residue depletion studies (206) with lactating cows orally or intravenously dosed with 220 mg radiolabeled sulfamethazine/kg bw showed that the milk collected within 0–48 h after dosing accounted for 1.1–2.0% of the administered radioactivity. Besides the parent compound, milk was found to contain two metab-olites: the N⁴-lactose conjugate of sulfamethazine and the N⁴ -acetylsulfametha-zine. A small amount of N⁴-acetylsulfamethazine was also present in all of the tissues at 48 h postdosing. The parent compound was the major residue in blood, skeletal muscle, and adipose tissues. Liver and kidney were also found to contain a series of more polar metabolites similar to those isolated in the urine. They were characterized as products of various metabolic processes including oxidation of the methyl group to hydroxymethyl group followed by sulfate ester or hexuro-nic acid conjugation, conjugation at the N¹-position with an hexoze or hexuronic acid, hydroxylation at the 3-position of the benzene ring followed by hexuronic acid conjugation, and cleavage of the N¹-C bond to yield sulfanilamide.

When lactating cows were dosed orally or intravenously with sulfametha-zine for 5 consecutive days (207), average concentrations of parent drug in the milk of the orally dosed cows were higher than in the milk of intravenously dosed cows during all stages of the withdrawal period. However, for both treatment groups, the concentration of the parent drug in milk decreased to less than 10 ppb at day 4 after the last dose. In addition, the concentrations of the N⁴ -lactose-and N⁴-acetylsulfamethazine decreased to less than 10 ppb in the milk at day 3 posttreatment.

In swine, the acetylation pathway of sulfamethazine is predominant; the 6-hydroxymethylsulfamethazine metabolite could not be detected in plasma, edible tissues, and urine because it was also excreted in the form of the acetylated metabolite (205). The N⁴-acetylsulfamethazine percentage in plasma and edible tissues of swine was relatively higher than that in calves, but its distribution pattern was similar in these two species. Other metabolites formed in swine were identified as the sulfamethazine-N⁴-glucocide and desamino-sulfamethazine metabolites (208). The highest N⁴-sulfamethazine concentrations were found in plasma, kidney, muscle, and liver tissue. Elimination of the parent drug and the N⁴-acetylsulfamethazine metabolite from swine organs and tissues was rapid when plasma levels were high (10–14 h half-life), but much slower at lower plasma levels (3–9 days half-life); a withdrawal period of approximately 18 days was considered appropriate to meet the generally accepted tolerance level of 0.1 ppm for sulfonamide residues (209).

Laying hens eliminate sulfamethazine rapidly by metabolic pathways that include both hydroxylation and acetylation (205). Within 3 days of the last sulfa-methazine administration, plasma concentrations of the drug and its metabolites fell below the level of 0.02 ppm. In eggs, increase of sulfamethazine in egg white and yolk occurs during the whole medication period. Residues of the parent drug could be detected in the eggs laid 7 days after the cessation of the administration (210). Traces of N⁴-acetylsulfamethazine and hydroxyl metabolites were also detectable up to day 3 after drug withdrawal.

When sheep were injected intravenously with a single dose of 107 mg sulfamethazine/kg bw, total residues in muscle, liver, kidney, and fat declined rapidly to reach, after 5 days of withdrawal, a value of less than 0.1 ppm (211).

In fish, the main metabolite is N⁴-acetylsulfamethazine, although sulfamethazine is hydroxylated and acetylated only to a small degree.

Sulfadimethoxine is a low-dose, rapidly absorbed, long-acting sulfonamide that is effective in reducing mortality due to bacterial infections and coccidiosis in poultry and ruminants (212, 213). The drug is highly protein-bound (80–85%) and this probably contributes to its slow excretion.

After oral administration of sulfadimethoxine to poultry at a dosage of 100 mg/kg bw for 5 days, the drug was slowly eliminated causing accumulation in plasma and particularly in liver and kidney (212). Sulfadimethoxine residues

could be reduced, however, to 0.1 ppm or less by day 8 after treatment in all chicken tissues, except kidney where they persist longer. This depletion profile is in line with that observed in another pertinent study (214). Following oral administration of the drug to young hens and turkeys, residues in tissues were undetectable at days 6 and 8 days, respectively (215). Significant levels of the N⁴-acetylsulfadimethoxine metabolite could also be found in plasma, tissues, and feces, the maximum percentage of acetylation being attained within 7 days after drug withdrawal.

When sulfadimethoxine was orally administered to laying hens at doses of 1.0 or 0.5 g/L water for 5 days, drug residues accumulated in eggs to a large extent (216). This was attributed to the longer time period over which albumen formation occurs (217). Maximum concentrations in egg white and yolk could reach levels of more than 30 ppm and 9 ppm, respectively, during such a medica-tion, but could also decline to below 0.1 ppm at day 4–6 or 7 posttreatment for egg white and yolk, respectively.

When sulfadimethoxine in addition to ormethoprim was administered through feed to Atlantic salmon for 5 consecutive days, plasma and tissue levels of both drugs reached steady-state levels between 3 and 8 days following initiation of medication (218). The highest average concentrations of sulfadimethoxine in plasma, muscle, liver, and kidney were 14.3, 17.7, 7.4, and 6.8 ppm, respectively, whereas the corresponding elimination half-lives were 20, 19, 62, and 45 h, re-spectively. On the other hand, the highest average concentrations of ormethoprim in plasma, muscle, liver, and kidney were 1.5, 3.7, 9.1, and 166.0 ppm, respec-tively, whereas the corresponding elimination half-lives were estimated at 63, 143, 95, and 410 h, respectively.

Sulfaquinoxaline, although largely superseded by more potent drugs, is still used for prevention and treatment of coccidiosis in turkeys, chickens, rabbits, and cattle. It is available as a powder for adding to drinking water or as a premix for inclusion in the feed for growth promotion purposes.

Feeding trials with rabbits orally administered 100 mg/kg bw sulfaquinoxa-line twice daily for 5 days showed that the drug was preferentially accumulated in kidney and liver (219). The highest residue concentrations were observed 4 days after the start of drug feeding, whereas a posttreatment period of 7–8 days was required to reach 0.1 ppm in liver, kidneys, and plasma.

Sulfathiazole is available for oral use and is also included in some paren-teral formulations in combination with other sulfonamides. It is also used as a feed additive for growth promotion purposes. It is more toxic than sulfamethazine and sulfadimethoxine but is safe when used as the phthalyl derivative.

Sulfathiazole has electrostatic properties similar to sulfamethazine, so that there is a tendency for nonmedicated feed to be contaminated during milling and on animal premises. These properties of the drug also make its use for treatment of foul brood in bees likely to contribute to the contamination of honey with

sulfathiazole residues, especially if it is used during the months when honey production is in progress.

Sulfathiazole is rapidly absorbed from the gut, and rapidly excreted in the urine of animals. It is readily metabolized and residues of acetylsulfathiazole, small amounts of other unidentified polar metabolites, and the parent drug were all detected in plasma and urine of ruminants following administration (220).

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 gastro-intestinal tract.

Baquiloprim has a high oral bioavailability in animals where it is widely distributed in the body and slowly eliminated (222,223). In cattle, baquiloprim was reported to have a much longer half-life and a larger volume of distribution than trimethoprim (223). Both urine and bile are important routes of elimination.

Baquiloprim is extensively metabolized in the target animals to a variety of metabolites including desmethylbaquiloprim, bis-desmethylbaquiloprim, ba-quiloprim-1-N-oxide, baquiloprim-3-N-oxide, and 6-hydroxybaquiloprim. A high percentage of the total residues in liver, kidney, and injection site is covalently bound.

Baquiloprim residue depletion studies in cattle treated by oral and parenteral route and in swine treated by parenteral route showed that 14–42 days after administration, the parent compound amounted to a very small proportion of the total residues in liver, kidney, and at the injection site. This was also the case with all identified metabolites. The concentrations of the residues in fat and normal muscle were too low to permit examination of their presence. However, pig skin contained a relatively high proportion of the parent compound. Pigs generally showed a faster degradation and elimination profile than cattle at com-parable times after administration, resulting in lower total and parent drug residue levels.

Trimethoprim, a structural analogue of the pteridine portion of dihydro-folic acid, is also a diaminopyrimidine derivative used extensively in food animal production for treatment of respiratory and alimentary tract infections. Although the half-life of trimethoprim is short in most species, when combined with a sulfonamide, particularly sulfadiazine or sulfadoxine, at a concentration ratio of 1 5, a pronounced clinical synergy is evident. Trimethoprim formulations are administered orally as a bolus, paste, or in the drinking water or in feed for calves, pigs, poultry, and fish at a dosage of 5 mg/kg bw. Parenteral formulations are also available for treatment of pigs, cattle, sheep, and goats at a dosage of up 3.8 mg/kg bw.