Residue depletion

NADA methods should be capable of reliably measuring an analyte (i.e., the marker residue) that has a defined quantifative relationship to the total residues of toxicological concern in the tissues of interest, namely the target tissue and muscle. The target tissue is generally the last tissue in which total residues deplete to the permitted maximum safe concentration. When the marker residue is at the tolerance, a defined unique concentration, the total residues have depleted to the respectively established safe concentrations in the target tissue and muscle. 

Because of its widespread therapeutic use and because the question of residues in food producing animals, SDM was selected for a study between species to compare its metabolism, the pharmacokinetics of the parent drug as well as its metabolites. Residue depletion studies were performed in edible tissues of calves, pigs and in the eggs of laying-hens. 

Residue depletion smdies with calves given intramuscular spectinomycin 30 mg/kg bw/day for 5 consecutive days showed that the average concentrations of the parent drug in liver, kidney, muscle, and fat were 4654, 43,053, 646, and less than 200 ppb, respectively, at 3 days, and 903, 2750, 200, and less than 27.1 ppb at 14 days after the last dose. 

Residue depletion studies in orally treated beef cattle showed that liver, kidney, and muscle contained 65-77 ppb, 50-115 ppb, and less than 20 ppb thiamphenicol, respectively, at 4 days after dosing, but less than 20 ppb at 10 days after dosing. Milk from dairy cows intramuscularly dosed with thiamphenicol contained residues 800 ppb 1 day after the cessation of treatment, but less than 20 ppb 48 h later. 

Residue depletion studies in sea bream administered once daily for 5 consecutive days feed medicated with 4 ppm thiamphenicol showed that residue... 

The pharmacokinetic characteristics of florfenicol have been described in goats (40), calves (41), and chickens (42). The efficacy of florfenicol in aquaculture has been also demonstrated against bacteria involved in some major fish pathologies, especially in salmon and trout (43, 44). Pharmacokinetic studies in Atlantic salmon indicated that the compound was well absorbed and distributed following oral administration (45). Tissue residue depletion studies after an oral daily administration of 10 mg/kg bw florfenicol in rainbow ftout at 10 C for 10 days showed that muscle/skin tissue contained 150 ppb drug at 15 days after the last dose (46). 

The presence of detectable levels in plasma and urine of treated cows indicates that nafcillin is absorbed systematically following intramammary administration. The major part of nafcillin is excreted in the milk, but a higher proportion of nafcillin is absorbed from the udder when nafcillin is administered at drying off. Residue depletion studies (70) with lactating cows showed that residues in all edible tissues were below 300 ppb at 72 h after cessation of treatment, while residues in milk were below 30 ppb from the fourth milking onwards, after cessation of the treatment. 

Residue depletion studies in dairy cows following intramuscular administration of 8.5 mg benzathine cephapirin/kg bw showed that residue levels in kidney, muscle, and liver were 1-5 ppm, less than 0.008-0.024 ppm, and less than 0.045 ppm, respectively, at 4.5 h postdosing (73). After intramuscular administration of 10 mg/kg bw sodium cephapirin to lactating cows, residue levels of 0.03-0.11 ppm were present in milk at 1-4 h, whereas 0.01 ppm were found from 4-8 h postdosing. In piglets, after intramuscular treatment witlr 20 mg/kg bw sodium cephapirin, residues could not be detected in liver, kidney, spleen, lung, and muscle at 24-120 h after treatment. 

Residue depletion studies in pigs after intramuscular administration of ceftiofur showed total residue concentrations of 590, 1190, 250, 400, and 1320 ppb in liver, kidney, muscle, skin/fat, and injection site, respectively, at 12 h after dosing. In cattle, intramuscular administration of radiolabeled ceftiofur resulted in total residue concentrations of 1294, 250, 60, and 60 ppb equivalents in liver 3508, 853, 159, and 159 ppb equivalents in kidney 208, 20, 10, and 10 ppb... 

Residue depletion studies (87) after intramammary administration of cefquinome to lactating cows showed that residues in edible tissues could be detected only in kidney at 24 h posttreatment and at concentrations below 200 ppb. High concentrations of cefquinome were found in milk at the first milking posttreatment, while at the 10th milking the residue concentrations in all milk samples were below 20 ppb. 

Residue depletion studies in pigs given intramuscularly the recommended treatment regimen showed that injection sites contained up to 208 ppb cefquinome 24 h after the last injection, declining to no measurable amounts at 144 h. Kidney contained 88-293 ppb at 24 h, but no measurable residues at 48, 72, and 120 h after the treatment. Liver, fat, skin, and muscle excluding the injection site were not found to contain detectable cefquinome up to 72 h after treatment. 

The main excretion pathway is through the urine in both calves and swine. Residue depletion studies did not showed detectable ( 0.01 ppm) residues in calves treated orally with 8 mg clavulanic acid-ampicillin formulation/kg bw for 3 days and slaughtered after 3 days or in calves, pigs, and sheep treated intramuscularly with 1.75 mg/kg bw for 5 days and slaughtered after 10, 7, and 14 days, respectively. 

Residue depletion studies in pigs fed 330 mg kitasamycin/kg feed for 14 days showed that at zero withdrawal only liver (100 ppb) and kidney (60 ppb) contained detectable residues. One day after withdrawal of the treatment, residual antibiotic activity was detectable only in the liver. Residue depletion studies in chickens fed 500 mg kitasamycin/kg feed for 14 days showed that at zero withdrawal only liver (70 ppb) contained detectable residues. One day after withdrawal, residual antibiotic activity could not be detected in any tissue. 

Residue depletion studies in chickens showed that 1 day after the end of treatment tire concentrations of the microbiologically active residues in liver, kidney, and fat/skin were490,240, and 330-41,810 ppb, respectively. Eggs from laying hens similarly treated contained residues ranged from less than 100 ppb to 450 ppb during treatment and at 3 days after treatment. 

Residue depletion studies in pigs showed that 2 days after the end of treatment the concentrations of microbiologically active residues in muscle, fat, skin, and kidney were from less than 100 ppb to 190 ppb, 4100 ppb, 780 ppb, and from less than 100 ppb to 1660 ppb, respectively. 

Residue depletion smdies in laying hens given oral boluses of 0.55 mg radiolabeled lincomycin/12 h for 12 days showed that residual radioactivity in whole eggs was in the range 1.2-12.0 ppb lincomycin equivalents during the treatment period, and in the range 1-4 ppb equivalents 3 days after treatment liver contained 141,24, and 6 ppb equivalents kidney 152, 21, and 6 ppb equiva-... 

Residue depletion studies with radiolabeled furazolidone have shown that the almost complete degradation of the drug in the body resulted in formation of a variety of protein-bound metabolites that were not solvent-extractable. Thus, when pigs were given radiolabeled furazolidone orally at 16.5 mg/kg bw/day for 14 days (123), total residual radioactivity in liver, kidney, muscle, and fat accounted for 41.1 ppm, 34.4 ppm, 13.2 ppm, and 6.2 ppm furazolidone equivalents, respectively, at zero withdrawal (132). Total residues were substantially lower by 21 days withdrawal, but were still in the ppm range at 45 days withdrawal. Extraction of the incurred muscle tissue at 0 and 45 days withdrawal with organic solvents led to removal of 21.8 and 13.7% of the total radioactivity, respectively. In contrast, 44 and 8.3% of the total radioactivity was extracted from liver on days 0 and 45, respectively. 

This nonextractable radioactivity was probably the result of covalent binding of the furazolidone intermediates to endogenous macromolecules. The bioavailability of these bound tissue residues from the above pig residue depletion study was determined by feeding rats lyophilized samples of liver and muscle tissues from animals sacrificed at 0 and 45 days after the last treatment (132). Results showed that the fraction of the bound residues bioavailable to rats was in the range 16-41%. The toxicological impact of these bioavailable bound residues has not been yet determined. 

Residue depletion studies in chickens showed that residues of danofloxacin in muscle declined from 36-90 ppb at 6 h to less than 25 ppb at 18 h after withdrawal of treatment. Residues of the A-desmethyl metabolite were less than 25 ppb at all time points. Residues of danofloxacin in liver declined from 157-319 ppb at 6 h to 18-66 ppb at 36 h after withdrawal of treatment. Residues of the A-desmethyl metabolite were 35-193 ppb and less than 10 ppb over the same time points. 

In a residue depletion study in cattle given the normal therapeutic treatment, residues of danofloxacin in liver declined from 372 ppb at 12 h after the last dose to 13 ppb at 5 days after the last dose. Over the same time period, residues at the injection site, kidney, and muscle declined from 669 ppb to less than 10 ppb, from 426 ppb to 5 ppb, and from 112 ppb to less than 10 ppb, respectively. Residues in most fat samples were below 10 ppb. 

Residue depletion studies in pigs given three daily intramuscular injections of 1.25 mg danofloxacin/kg bw showed that residues of the parent drug in liver were 27 ppb at 2 days after the last dose and below 10 ppb at later time points. Mean danofloxacin concentrations in kidney declined from 36 ppb at 2 days after the last dose to 5.5 ppb at 6 days after the last dose and to below 5 ppb at later time points. Two days after the last dose, mean danofloxacin concentrations in muscle, fat, and at the injection site were 15 ppb, below 5 ppb, and 17 ppb, respectively at later time points residues could not be detected. Residues of A-... 

Residue depletion studies in chickens and turkeys orally dosed with 10 mg enrofloxacin/kg bw for 7 days showed that the sum of enrofloxacin and ciprofloxacin, which has been designated as the market residue for regulatory purposes, in the chicken liver declined from 42 ppb at 3 day withdrawal to 11 ppb at 15 day withdrawal in turkeys, the level of the marker residue in liver... 

The residue depletion profile of flumequine in uout seems to be quite similar to that in the sea bass (174). When flumequine was administered to seabass as a mixture with the feed at a dosage of 12 mg/kg bw for 5 days, residues of flumequine in muscle tissue could be detected by 36 h after the last treatment. The relatively high temperature of the sea water (21-25.3 C) in this study was suggested as the primary factor determining the rapid depletion of residues from the fish tissue. In another study (175), flumequine disappeared from muscle of sea bream at 240 h after the end of treatment, but showed a longer depletion rate from skin and vertebrae that behaved in fact as reservoir tissues. Much slower depletion profiles have been reported in studies carried out with Atlantic salmon (158, 170, 176), rainbow trout (177), and some wild fish caught in the vicinity of fish farms such as saithe and cod (178). 

When pigs and calves were subcutaneously given marbofloxacin, residues persisted in liver and kidney for up to 4 days posttreatment. Almost all of the residues detected in muscle and fat were due to the parent drug, whereas residues in liver and kidney were also due to drug-related metabolites as well. Residue depletion studies in dairy cows similarly treated showed that a proportion of 73-89% of the total residues in the milk was due to the parent marbofloxacin. 

In aquaculture, the salinity of the surrounding water appears to affect the pharmacodynamics of oxolinic acid in fish. Thus, the residue depletion profile of oxolinic acid in seawater coho salmon was similar to that observed in various seawater fish such as Japanese mackerel, red sea bream, yellowtail, and flounder... 

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. 

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 comparable times after administration, resulting in lower total and parent drug residue levels. 

Residue depletion studies in cattle, swine, sheep, chickens, and turkeys given oral forms of oxytetracycline including feed premixes, soluble powders, and tablets showed that residues in all edible tissues, with the exception of kidney, were cleared of detectable amounts of oxytetracycline within 5 days postdose. Injectable forms of oxytetracycline yielded higher residue levels that persisted longer than the oral forms, while long-acting formulations of oxytetracycline required extended withdrawal periods (234). 

Residue depletion studies of rifaximin in lactating cows or in cows at drying off showed that the drug could not be detected (detection limit, 0.01 ppm) in plasma or milk following intramammary treatment. Oral or topical administration of rifaximin also led to a negligible systemic absorption of the active ingredient. 

Following therapeutic treatment, thiophanate residues are higher in liver, with significant levels also being present in kidney relatively lower concentrations are detected in the other edible tissues (9). Residue depletion studies in sheep given a single oral dose of 100 mg thiophanate/kg bw showed that the mean thiophanate residue concentrations in liver, kidney, muscle, and fat were 930, 1,060, 670, and 2930 ppb, respectively, after 1 day, and below 100 ppb on days 3 and 7 after dosing. 

Residue depletion studies in swine given an infeed medication of 75 mg thiophanate/kg bw/day showed mean thiophanate concentrations in liver, kidney, muscle, and skin/fat of 5550, 6600, 2600, and 16,200 ppb, respectively, at 1 day after dosing, and 180, 100, less than 100, and 250 ppb, respectively, at 3 days after dosing. However, residue concentrations were below 100 ppb in all tissues at 7 day withdrawal. 

Residue depletion studies in lactating cows given a single oral dose of 100 mg thiophanate/kg bw showed mean thiophanate residue concentrations of 440, 320, and 140 ppb in tlie milk collected at 6 h, 20 h, and 30 h milkings, respectively (9). However, milk collected at 44 h and thereafter was not found to contain detectable (detection limit 50 ppb) residue concentrations. 

In a study on pigs treated with fenbendazole at 5 mg/kg bw, a concentration of 0.28 ppm of the parent drug was found in the liver at 7 day withdrawal other tissues were free of detectable fenbendazole residues. Residue depletion studies in fenbendazole-treated cattle at 10 mg/kg bw showed the presence of 8.4 ppm of the parent drug in liver, 1.04 ppm in kidney, 0.47 ppm in muscle, and 0.95 ppm in fat at 2 day withdrawal however, at 7 day withdrawal, only liver was found to contain residues at a level of 0.67 ppm (10). 

A residue depletion study (15) in rainbow trout given both oral and bath treatments of fenbendazole, at a water temperature of 12 C, showed that the drug was partly metabolized to fenbendazole sulfoxide. Both fenbendazole and fenbendazole sulfoxide were found to accumulate in fish skin. However, both the parent drug and its metabolite were largely depleted within 96 and 24 h, respectively, posttreatment. Formation of the sulfone metabolite was not detected in any fish tissue. 

For cattle and sheep, liver is the tissue with the highest concentration of drug-related residues. Liver is also the tissue that exhibits the slowest rate of residue depletion. The extractable portion of the residue present in liver consists of oxfendazole, fenbendazole sulfone, and fenbendazole. A large portion of the residue present in liver is not extractable and this proportion increases with time after dosing. Evidence has been presented that bound oxfendazole residues have low bioavailability (10). 

Residue depletion studies in cattle showed that liver residue concentrations declined gradually from 55.5 ppb at 10 day postdosing to below 10 ppb by 18 days after treatment (10). Residue depletion studies in sheep showed that liver residue concentrations declined gradually from 476 ppb at 10 day post-dosing to 12 ppb by 24 days after treatment. 

---