Tilmicosin in cattle

DONOIIO ET AL. Tilmicosin in Cattle Metabolism and Tissue Residues 161 Tissue Residue Studies... 

In cattle, treatment consists of 10 mg tilmicosin/kg bw as a single injection administered subcutaneously in the neck. This results in long-lived serum and tissue tilmicosin levels. Cattle dosed with radiolabeled tilmicosin excreted most... 

After oral administration of radiolabeled tilmicosin to broilers at dosage in tire range 25-450 mg/L in water for 3-5 days, radioactivity was mainly distributed to liver and kidney and, to a lesser extent, to muscle and fat. The parent drug was the main residue in tissues, excreta, and bile, but partly desmethylated, hy-droxylated, reduced, and sulfated metabolites could be also identified. Similar pharmacokinetic characteristics were also observed in cattle, swine, and sheep. In broilers treated with tilmicosin at the recommended dosage, residues of the parent drug in liver were 2.6 ppm at day 3 declining to 0.13 ppm at day 17 residue levels in kidney averaged 0.65 ppm at day 3 and declined via 0.08 ppm on day 10 to below 0.06 ppm thereafter. Residues in muscle, fat, and skin were approximately 0.10 ppm at day 3 and less than 0.014 ppm after day 14. 

A second new semi-synthetic macrolide is tilmicosin, which inhibits a variety of animal pathogens including species of Pasteurella [295]. It is effective for both treatment and prophylaxis of respiratory infections in cattle after a single injection due to its long in vivo half-life and has been registered for the treatment of bovine respiratory disease [296-299]. Tilmicosin is also orally bioavailable and has treated pneumonia due to Pasteurella and Actinobacillus in pigs when incorporated into feed [300, 301]. 

The macrolide antibiotics include erythromycin, clarithromycin, azithromycin, tylosin, tilmicosin and tiamulin. Clindamycin and lincomycin are related lincosamides. Susceptible bacteria include staphylococci, streptococci, Campylobacter jejunii, Clostridium spp., R. equi, Mycoplasma pneumoniae and Chlamydia spp. Drugs in this group are only effective against a few Gram-negative bacteria in cattle, namely some strains of Pasteurella and Haemophilus spp. Macrolides and lincosamides are associated with causing colitis in horses, so their use is usually restricted to p.o. erythromycin for the treatment of R. equi infections in foals. Subantimicrobial doses of erythromycin are administered i.v. to horses for gastrointestinal prokinetic action. 

Tilmicosin, (20-deoxo-20-(3,5-dimethylpiperidin-l-yl)-desmycosin) is a new macrolide antibiotic which is being developed for treatment of bovine respiratory disease by single subcutaneous injection into cattle. Excretion, tissue residue, and metabolism studies were conducted with " C-tilmicosin-treated cattle and rats. Radioactivity was excreted primarily in the feces after parenteral dosing of cattle and oral dosing of rats. Among edible tissues from treated cattle, liver and kidney contained the highest concentrations of radioactivity. The most abundant metabolite was N-desmethyl tilmicosin. Comparative metabolism studies with cattle and rats indicated that the pattern of metabolism was the same for both species. 

Three tissue residue studies were conducted to characterize the pattern of residues in cattle treated with tilmicosin. In the first study, four steers and one bull calf weighing 157 to 202 kg were injected subcutaneously with 20 mg/kg Pip- " C-tilmicosin. One calf was euthanized 3 days after dosing, two were euthanized at 21 days, and two at 56 days after dosing. Total RA was measured in muscle, liver, kidney, fat, injection site, lung, and bile. In addition, blood was collected from one calf at 4, 8, 24,48,... 

Table III. Tilmicosin Tissue Residue Decline Study in Cattle Injected with 10 mg/kg Unlabeled Tilmicosin...

The presence of increased concentrations of compound T-2 relative to tilmicosin in livers from cattle which were injected with tilmicosin has been noted above. This presence of T-2 beyond trace levels was not observed in livers of orally treated rats (Figure 6). 

The JECFA has allocated ADIs for erythromycin, spiramycin, tilmicosin, and tylosin, with those values for erythromycin, spiramycin, and tylosin based on microbiological endpoints. The CAC also established MRLs for erythromycin in muscle, liver, kidney, and fat of chickens and turkeys, and in chicken eggs for spiramycin in muscle, liver, kidney, and fat of cattle, pigs, and chickens for tilmicosin in muscle, liver, kidney, fat (or fat/skin) of cattle, sheep, pigs, chickens, and turkeys and MRLs for tylosin in muscle, liver, kidney, fat of cattle, pigs and chickens, and in chicken eggs." Details of residue smdies considered by JECFA are contained in monographs prepared for erythromycin, spiramycin, tilmicosin, " and tylosin. ... 

After intravenous dosing, the half-life of tylosin is short in all species, 1.1, 2.1, 3.0, and 4.0 h, respectively, in calves, sheep, goats, and pigs." ° Tylosin penetrates readily into milk and is slowly cleared from the mammary gland, so that its use in lactating cattle is not recommended. In fact, this property extends to other macrolides, due to their basic nature and lipophilic properties. For example, the half-life of tilmicosin in cows is approximately 1 h, but concentrations in milk exceed 0.8 mg/1 for 8-9 days after a single subcutaneous dose of 10 mg/kg. 

Reductive amination of the aldehyde group to aminomethyl derivatives has provided another route to potentially useful compounds. An initial report described the synthesis of primary amino derivatives of tylosin and leucomycin along with dimeric structures of each [140]. A group of derivatives of tylosin and demycarosyltylosin (desmycosin) were subsequently synthesized and shown to retain antimicrobial activity [141]. From a more extensive series of compounds prepared by reductive amination of tylosin and related macrolides, 20-deoxo-20-(3,5-dimethylpiperidinyl)desmycosin was selected for further development in veterinary medicine [142]. This compound, under the generic name of tilmicosin (see Fig. 7), is being evaluated for treatment of pneumonia in cattle and pigs [143, 144, 145]. 

Modric, S. Webb, A.I. Derendorf, H. Pharmacokinetics and pharmacodynamics of tilmicosin in sheep and cattle, J.vet.Pharmacol.Therap., 1998, 21, 444-452. 

Tilmicosin is a macrolide antibiotic exclusively used in veterinary medicine and resembling tylosin. It is approved for treatment of respiratory diseases in beef cattle and sheep by the subcutaneous route (100, 101). It is also indicated for treatment and control of respiratory diseases associated with mycoplasma in broiler chickens, but not in laying hens. Of major significance is that in contrast to other macrolides, tilmicosin is not safe for use in swine since fatalities may occur at dosage as low as 20 mg/kg bw (7). 

Tilmicosin, C HgoN O, was selected as a therapeutic agent to treat pneumonia m cattle and pigs because of its activity against Pasturelle species, oral bio avail ability, and prolonged concentrations in vivo. 

Tilmicosin, Figure 1, is a new semisynthetic antibiotic derived from the macrolide antibiotic tylosin. The synthesis and antibacterial activity of tilmicosin have been described by Debono, et al. and Kirst, et al. (/-4). Tilmicosin has in vitro activity against a variety of Gram positive and Gram negative bacteria, as well as mycoplasma species. It is effective for treatment of bovine respiratory disease caused by Pasteurella haemolytica when administered as a single subcutaneous injection (5, 6). This paper describes the excretion, tissue residue pattern, and metabolism of tilmicosin when injected into cattle, and also gives comparative metabolism data from rats which were dosed orally. 

Table I. Residues of Radioactivity (Mean PPM) in Tissues of Cattle Injected with 20 mg/kg of Pip- C-Tilmicosin...

In the third tissue residue study, twelve cattle, eight steers, and four heifers, weighing approximately 200 kg, were dosed with 10 mgAg unlabeled tilmicosin. Groups of 2 steers and one heifer were euthanized at 14, 28, 35, and 42 days after treatment. Muscle, liver, kidney, fat, and injection site samples were collected and assayed for parent tilmicosin. The mean residue concentrations are shown in Table III. 

These were, parent tilmicosin, metabolite T-1, which eluted just before tilmicosin, and compound T-2, which eluted after tilmicosin. Metabolite T-1 constituted 16% and 8% of the liver RA at 3- and 28-days, respectively. Compound T-2 constituted 9% and 21% in the same samples. Metabolite T-1 was later identified as N-desmethyl tilmicosin. Compound T-2 was found to be a minor impurity in the dosing material, rather than a true metabolite. Characterization of T-1 and T-2 are described in a later section. Residues in livers of the 42- and 56-day withdrawal cattle were too low for this type of fractionation. 

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