Macrolide

Absorption, Distribution and Excretion
Pigs were given a dose of 154 or 400 mg (14)C-tilmicosin in the diet following a similar dose given for 5 days. The recovery of radioactivity was 4 to 6% in urine and 62 to 75% in feces. Radioactivity was detected in the bile but was not quantified.
Pigs were administered a dose of 110 mg (14)C-tilmicosin in the diet over the course of one day. The recovery of radioactivity was 15% in the urine and 80% in the feces.
Tilmicosin is administered SC. Absorption after injection is rapid ... .
Beulah cross lambs were administered a single subcutaneous dose of 20 mg/kg bw per day (14)C-tilmicosin. The major radioactive component in the liver, kidneys and urine was the parent drug, together with lesser amounts of T1 and T2, and minor amounts of other unidentified substances.
For more Absorption, Distribution and Excretion (Complete) data for TILMICOSIN (13 total), please visit the HSDB record page.

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Metabolism / Metabolites
Beulah cross lambs were administered a single subcutaneous dose of 20 mg/kg bw per day (14)C-tilmicosin. The major radioactive component in the liver, kidneys and urine was the parent drug, together with lesser amounts of T1 and T2, and minor amounts of other unidentified substances.
Fischer-344 rats (10 males and 10 females) were given gavage doses of 50 mg/kg bw per day (14)C-tilmicosin for 5 days. An analysis of fecal radioactivity for the presence of the sulfate metabolite that was found in the feces of pigs revealed the presence of a similar compound, but quantification was not undertaken.
Tilmicosin, labelled with (14)C in both the desmycosin macrolide ring and the piperidine ring, was given orally to 15 male and 15 female Fischer-344 rats. The dosage was 20 mg/kg bw per day for 3 days. In the liver, radiolabel corresponded to tilmicosin and a desmethyl derivative, T1 (demethylated in the mycaminose ring). The single radioactive substance identified in urine was unchanged tilmicosin, while in feces the major peak was parent compound with lesser amounts of desmethyl tilmicosin and a high molecular weight compound known to be present as an impurity in the administered substance, T2 (consisting of two macrolide rings and one piperidine ring).
In a summary of results obtained in cattle injected with (14)C-tilmicosin, it was reported that the radioactivity profile in the liver of treated rats was similar to that in the feces. In animals treated with a highly purified sample of tilmicosin, metabolite T2 was not detected in the liver, suggesting that its presence was a result of direct administration as a component of the drug substance. Radioactivity in the kidneys was essentially in the form of unchanged tilmicosin.
For more Metabolism/Metabolites (Complete) data for TILMICOSIN (6 total), please visit the HSDB record page.

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Biological Half-Life
The plasma half-lives of macrolides usually are 1-3 hr, ... /Macrolides/

Interactions
Concurrent use /of carbamazepine, cyclosporine, digoxin, hexobarbital, phenytoin or valproic acid/ with macrolide antibiotics has been associated with increased serum concentration of these medications; monitoring of serum concentrations of medications administered concurrently is recommended to avoid toxicity. /Macrolide antibiotics/
Concurrent use of the xanthines (except dyphylline) with macrolides may decrease hepatic clearance of xanthines, resulting in increased serum concentrations and/or toxicity; dosage adjustment of the xanthines may be necessary during and after therapy with macrolides. /Macrolide antibiotics/
Concurrent use /of midazolam or triazolam/ with macrolide antibiotics may decrease the clearance of these medications, increasing the pharmacologic effect of midazolam or triazolam. /Macrolide antibiotics/
Concurrent administration with macrolide antibiotics has been associated with increased anticoagulant effects; prothrombin time should be monitored carefully in patients receiving anticoagulants and macrolides concurrently. /Macrolide antibiotics/
For more Interactions (Complete) data for TILMICOSIN (8 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat (non-fasted-male & female) oral > 2000 mg/kg/bw
LD50 Rat (fasted-female) oral 800 mg/kg/bw
LD50 Rat (fasted-male) oral 850 mg/kg/bw
LD50 Mouse (female) sc 109 mg/kg/bw
For more Non-Human Toxicity Values (Complete) data for TILMICOSIN (8 total), please visit the HSDB record page.

[1]. Micotil 300 New Animal Drug Application.

Tilmicosin is a macrolide antibiotic with formula C46H80N2O13. It is used for the treatment of respiratory disease in cattle at high risk of developing bovine respiratory disease associated with Mannheimia haemolytica. It has a role as a cardiotoxic agent, an antibacterial drug and a calcium channel blocker. It is a macrolide antibiotic, a monosaccharide derivative and an enone.
Tilmicosin is a macrolide antibiotic. It is used in veterinary medicine for the treatment of bovine respiratory disease and ovine respiratory disease associated with Mannheimia haemolytica.
See also: Tilmicosin Phosphate (has salt form); Tilmicosin; Tilmicosin Phosphate (component of).

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Mechanism of Action
Tilmicosin has in vitro activity against gram-positive organisms and mycoplasma and is active against certain gram-negative organisms, such as Hemophilus somnus, Mannheimia (Pasteurella) hemolytica, and Pasteurella multocida. However, M. hemolytica is more sensitive than P. multocida to tilmicosin. Other gram-negative organisms tested, including Enterobacter aerogenes, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella, and Serratia species, are very resistant to tilmicosin. Some strains of Actinomyces also are extremely resistant to tilmicosin.
The antimicrobial mechanism seems to be the same for all of the macrolides. They interfere with protein synthesis by reversibly binding to the 50 S subunit of the ribosome. They appear to bind at the donor site, thus preventing the translocation necessary to keep the peptide chain growing. The effect is essentially confined to rapidly dividing bacteria and mycoplasmas. Macrolides are regarded as being bacteriostatic, ... . Macrolides are significantly more active at higher pH ranges (7.8-8). /Macrolides/
Macrolides have been reported to modify the host immune and inflammatory responses both in vivo and in vitro. /The authors/ examined the in vitro effect of the macrolides tilmicosin and tylosin, which are only used in the veterinary clinic, on the production of nitric oxide (NO), prostaglandin E2 (PGE2) and cytokines by lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and mouse peripheral blood mononuclear cells (PBMCs). Compared with 5 ug/mL, tilmicosin and tylosin concentrations of 10 ug/mL and 20 ug/mL significantly decreased the production of 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha), PGE2, NO, tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta and IL-6, and increased IL-10 production. Cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) gene expression were also significantly reduced. These results support the opinion that macrolides may exert an anti-inflammatory effect through modulating the synthesis of several mediators and cytokines involved in the inflammatory process.

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Therapeutic Uses
MEDICATION (VET): Tilmicosin is available as an injectable formulation for the treatment of respiratory diseases in cattle and sheep and as a feed premix for the treatment and control of respiratory diseases in pigs.
THERAP CAT (VET): Antibacterial
MEDICATION (VET):The macrolides are used to treat both systemic and local infections. They are often regarded as alternatives to penicillins for the treatment of streptococcal and staphylococcal infections. General indications include upper respiratory tract infections, bronchopneumonia, bacterial enteritis, metritis, pyodermatitis, urinary tract infections, arthritis, and others. Formulations for treating mastitis are also available and often have the advantage of a short withholding time for milk. /Macrolides/
MEDICATION (VET): Tilmicosin is a macrolide antibiotic synthesized from tylosin. It has an antibacterial spectrum similar to tylosin with enhanced activity against Pasteurella multocida and Pasteurella hemolitica. Tilmicosin is recommended for the treatment of bacterial pneumonia in young cattle ... .
For more Therapeutic Uses (Complete) data for TILMICOSIN (8 total), please visit the HSDB record page.

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Drug Warnings
/VET/: Tilmicosin is not labeled for use in female dairy cattle 20 months of age or older, veal calves, calves less than 1 month of age, or calves fed an all-milk diet.
Toxicity and side effects are uncommon for most macrolides (except tilmicosin), although pain and swelling may develop at injection sites. Hypersensitivity reactions have occasionally been seen. ... Horses are sensitive to macrolide-induced GI disturbances that can be serious and even fatal. ... Tilmicosin is characterized by cardiac toxicity (tachycardia and decreased contractility). It is contraindicated in swine and should not be used in an extra-label manner. cattle hae died after IV injection of tilmicosin.
Tilmicosin: All species: To avoid cardiotoxicity, tilmicosin should not be administered intravenously. Human: Injection of tilmicosin may be lethal. Although there is little information on the effects of tilmicosin in people, a variable susceptibility to cardiotoxic reactions in other species warrants caution with human exposure and close monitoring of the cardiovascular system, particularly after accidental injection. A physician should be consulted immediately in cases of accidental injection. Dogs: In laboratory dogs, tachycardia and decreased cardiac contractility have been noted in response to tilmicosin injection. Goats: Administration of tilmicosin to goats at intramuscular or subcutaneous doses >10 mg per kg of body weight (mg/kg) is likely to lead to toxicity. Horses: Administration of tilmicosin to horses at intramuscular or subcutaneous doses >10 mg/kg is likely to lead to toxicity. Pigs: Injection of tilmicosin into swine can be fatal as a result of cardiovascular toxicity. Administration of epinephrine to treat cardiovascular toxicity due to intravenous tilmicosin administration has been associated with an increased risk of death.
/VET:/ In cattle, tilmicosin is distributed into milk at effective antibacterial concentrations for susceptible pathogens, but detectable concentrations in milk are maintained for many weeks (up to 42 days). Tilmicosin should not be administered to lactating dairy cattle because of impractical withdrawal times.

C46H80N2O13

869.13

868.566

108050-54-0

Tilmicosin phosphate;137330-13-3;Tilmicosin-d3

5282521

White to off-white solid powder

1.2±0.1 g/cm3

926.6±65.0 °C at 760 mmHg

514.2±34.3 °C

0.0±0.6 mmHg at 25°C

1.545

4.95

4

15

12

61

1420

19

CC[C@@H]1[C@H](/C=C(/C=C/C(=O)[C@@H](C[C@@H]([C@@H]([C@H]([C@@H](CC(=O)O1)O)C)O[C@H]2[C@@H]([C@H]([C@@H]([C@H](O2)C)O)N(C)C)O)CCN3C[C@@H](C[C@@H](C3)C)C)C)\C)CO[C@H]4[C@@H]([C@@H]([C@@H]([C@H](O4)C)O)OC)OC

JTSDBFGMPLKDCD-XVFHVFLVSA-N

InChI=1S/C46H80N2O13/c1-13-36-33(24-57-46-44(56-12)43(55-11)40(53)31(8)59-46)19-25(2)14-15-34(49)28(5)20-32(16-17-48-22-26(3)18-27(4)23-48)42(29(6)35(50)21-37(51)60-36)61-45-41(54)38(47(9)10)39(52)30(7)58-45/h14-15,19,26-33,35-36,38-46,50,52-54H,13,16-18,20-24H2,1-12H3/b15-14+,25-19+/t26-,27+,28-,29+,30-,31-,32+,33-,35-,36-,38+,39-,40-,41-,42-,43-,44-,45+,46-/m1/s1

(4R,5S,6S,7R,9R,11E,13E,15R,16R)-6-[(2R,3R,4S,5S,6R)-4-(dimethylamino)-3,5-dihydroxy-6-methyloxan-2-yl]oxy-7-[2-[(3S,5R)-3,5-dimethylpiperidin-1-yl]ethyl]-16-ethyl-4-hydroxy-15-[[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyloxan-2-yl]oxymethyl]-5,9,13-trimethyl-1-oxacyclohexadeca-11,13-diene-2,10-dione

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 100 mg/mL (115.06 mM)
1M HCl: 100 mg/mL (115.06 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (2.88 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 2.5 mg/mL (2.88 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (2.88 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)