Tilmicosin

Molecular formula C46 Hso Nj 3 Molecular weight 869.13 CAS Registry No 108050-54-0 Merck Index 13,9516 

Sample preparation Condition a 500 mg Bond Elut CIS SPE cartridge with MeOH and water. Add 2 mL serum to the SPE cartridge, wash with water, wash with 5% ammonium hydroxide, wash with water, elute with 2 mL MeOH acetic acid 5 95. Evaporate the eluate to dr5mess under a stream of nitrogen, reconstitute the residue with 1 mL diluent, inject an ahquot. (The diluent was MeOH water l M dibutylammonium phosphate 50 47.5 2.5.) 

Mobile phase Gradient. A was MeCN water 50 50 adjusted to pH 2.5 with orthophos-phoric acid. B was water adjusted to pH 2.5 with orthophosphoric acid. C was 168 mL dibutylamine in 700 mL water, adjust to pH 2.5 with orthophosphoric acid, make up to 1 L with water. A B C 100 0 0 for 3 min, to 55 30 15 over 1 min, maintain at 55 30 15 for 7 min, return to initial conditions over 1 min, re-equihbrate for 8 min. 

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

---

This selected ion monitoring (SIM) approach typically has greater applicability in cases where sensitivity is more of a concern. Kiehl and Kennington developed a swine liver confirmatory method for tilmicosin that confirmed structure based upon monitoring a parent ion and two additional structural fragment ions. A discussion of the validation requirements for confirmatory methods is provided in Section 6. 

Tiller s guide, for selecting SLS equipment, 11 347-348 Tilmicosin, 15 301 Tilted plate separators, 22 68, 69 Tilting press, 12 731-732 Timberol, 24 566 Timber products... 

Spiramycin, kitasamycin, josamycin, desmycosin, mirosamycin, tilmicosin, and tylosin are examples with a 16-membered ring. Spiramycin consists of three components spiramycin I, II, and III spiramycin I is the major component. Kitasamycin consists of several components leucomycin Ai, A3 9, and A, the leucomycin A5 being the major component (89). losamycin is identical to the leucomycin A3 (90), while tylosin consists of four components, tylosin A, B, C, and D, the major component being tylosin A. Tylosin B is identical to desmycosin. 

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). 

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... 

Because of this slow kinetic excretory pattern, tilmicosin is contraindicated for use in lactating animals. Rapid and extensive penetration of tilmicosin from blood into milk and slow elimination from the milk arc among the characteristic kinetic features of the drug after intravenous and subcutaneous administration (103). 

When tilmicosin was administered to six lactating cows as a single subcutaneous dosage of 10 mg/kg (104), residues in milk were higher than 25 ppb from 19 to 31 days postdosing. Following subcutaneous administration to sheep, a maximum concentration of 10247 ppb of tilmicosin was observed in milk at 8 h after dosing by day 12, however, the concentration of tilmicosin was below the MRL of 50 ppb. The half-life of tilmicosin in milk was calculated to be approximately 24 h (105). 

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. 

Tilmicosin 556.735 Tilmicosin (marker) Cattle Liver (target) — 1200... 

In addition, a number of other assays have been developed for screening antibiotic residues in body fluids of animals at slaughter. They include an agar plate assay for detecting tilmicosin in bovine serum (88), modified CFT and BR-test assays for screening penicillin G residues in plasma of healthy steers (89), a modified CFT for screening plasma and urine samples from healthy market... 

Tire preferred type of reversed-phase sorbents is Cjg bonded silica (Table 29.4). Using this reversed-phase sorbent, ion-pair separation of lincomycin (154), spiramycin (138), and tylosin (145) residues has also been reported through use of octanesulfonate, heptanesulfonate, and tetrabutylammonium pairing ions, respectively. Phenyl-bonded silica or polymeric stationary phases have also been described for the separation of tilmicosin (133) and lincomycin (146) residues, respectively. 

In liquid chromatographic analysis of macrolides and lincosamides, most popular is the ultraviolet detector (Table 29.4). Tylosin, tilmicosin, spiramycin, sedecamycin, and josamycin exhibit relatively strong ultraviolet absorption, but erythromycin, lincomycin, pirlimycin, and oleandomycin show extremely weak absorption in the ultraviolet region. Hence, detection at 200-210 nm has been reported for the determination of lincomycin (146). However, a combination of poor sensitivity and interference from coextractives necessitated extensive cleanup and concentration of the extract. Precolumn derivatization of pirlimycin with 9-fluorenylmethyl chloroformate has also been described to impart a chromophore for ultraviolet detection at 264 nm (140). 

Electrochemical detection is better suited to the analysis of erythromycin and lincomycin. This method of detection has been applied for the determination of erythromycin A (139) and lincomycin (154) residues in salmon tissues. Liquid chromatography coupled with mass spectrometry is particularly suitable for confirmatory analysis of the nonvolatile macrolides and lincosamides. Typical applications of this technique are through thermospray mass spectrometry, which has been used to monitor pirlimycin in bovine milk and liver (141,142), and chemical ionization, which has been applied for identification of tilmicosin (151) in bovine muscle, and for identification of spiramycin, tylosin, tilmicosin, erythromycin, and josamycin residues in the same tissue (150). 

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. 

A more difficult preseparation technique was used for the determination of TLM in ovine milk, combining several LLE procedures. Tilmicosin was extracted from milk into MeOH and acidified, and nonpolar coextractives were removed using hexane followed by carbon tetrachloride. pH was adjusted to 9.0, and TLM was partitioned into chloroform. Recoveries achieved were 84.3-104.8%, with RSD values of 6.6-12.9% (126). 

W Chan, GC Gerhardt, CDC Salisbury. Determination of tylosin and tilmicosin residues in animal tissues by reversed-phase liquid chromatography. J AOAC Int 77 331-333, 1994. 

MA Ngoh. Determination of tilmicosin in bovine milk by liquid chromatography with ultraviolet detection. J AOAC Int 79 652-655, 1996. 

RM Parker, RKP Patel. Determination of tilmicosin in ovine milk using high-performance liquid chromatography. Analyst 119 2577-2579, 1994. 

Micotil or Tilmicosin 127, a 1-substituted 3,5-lupitidine (85 15 mixture of dsjtrans-isomers), is used as an antibacterial agent against calf pneumonia. The macrolide component of micotil is structurally related to the antibacterial compound tylosin <1993JAVMA273>. 

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]. 

---