Macrolide

Absorption, Distribution and Excretion
Pigs were fed 154 or 400 mg (14)C-tilmicosin in their diet for 5 consecutive days at the same dose. Radioactivity recovery in urine was 4% to 6%, and in feces 62% to 75%. Radioactivity was detected in bile, but not quantitatively analyzed. Pigs were fed 110 mg (14)C-tilmicosin in their diet for one day. Radioactivity recovery in urine was 15%, and in feces 80%. Tilmicosin was administered subcutaneously. Absorption was rapid after injection… Biura crossbred lambs were subcutaneously injected daily with 20 mg/kg body weight of (14)C-tilmicosin. The main radioactive components in the liver, kidneys, and urine were the parent drug, along with small amounts of T1 and T2, and small amounts of other unidentified substances. For more complete data on absorption, distribution, and excretion of tilmicosin (13 items in total), please visit the HSDB records page.

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Metabolism/Metabolites
Beulah hybrid lambs were subcutaneously injected daily with 20 mg/kg body weight of (14)C-tilmicosin. The main radioactive components in the liver, kidneys, and urine were the parent drug, along with small amounts of T1 and T2, and small amounts of other unidentified substances.
Fischer-344 rats (10 males and 10 females) were administered 50 mg/kg body weight of (14)C-tilmicosin by gavage for 5 consecutive days. Fecal radioactivity analysis of sulfate metabolites found in pig feces indicated the presence of a similar compound, but quantification was not performed.
15 male and 15 female Fischer-344 rats were orally administered tilmicosin labeled with ¹⁴C (both the desmycophenolate macrolide ring and piperidine ring were labeled) at a dose of 20 mg/kg body weight/day for 3 consecutive days. In the liver, the radiolabeled material corresponds to tilmicosin and its demethylated derivative T1 (mycophenolate ring demethylation). The only radioactive material detected in urine was unmetabolized tilmicosin, while the main peak in feces was the parent compound, with smaller amounts of demethylated tilmicosin, and a high molecular weight compound T2 (composed of two macrocyclic lactone rings and a piperidine ring) known as an impurity in the administered substance. A summary of results from studies on cattle injected with 14C-tilmicosin indicates that the radioactive distribution in the liver of tested rats was similar to that in feces. In animals treated with high-purity tilmicosin samples, metabolite T2 was not detected in the liver, suggesting its presence was due to direct administration of the drug component. Radioactive material in the kidneys was primarily present as unmetabolized tilmicosin. For more complete metabolite/metabolite data on tilmicosin (6 metabolites), please visit the HSDB record page.

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Biological Half-Life
The plasma half-life of macrolide drugs is typically 1-3 hours, .../Macrolides/

Interactions
Carbamazepine, cyclosporine, digoxin, hexobarbital, phenytoin, or valproic acid, when used concomitantly with macrolide antibiotics, may increase the serum concentrations of these drugs; monitoring the serum concentrations of concomitant drugs is recommended to avoid toxicity. /Macrolide Antibiotics/
Xanthines (except dihydroxypropyltheophylline) may decrease the hepatic clearance of xanthines when used concomitantly with macrolides, leading to increased serum concentrations and/or toxicity; dose adjustments of xanthines may be necessary during and after macrolide treatment. /Macrolide Antibiotics/
Midazolam or triazolam may decrease the clearance of macrolide antibiotics when used concomitantly with macrolides, thereby enhancing the pharmacological effects of midazolam or triazolam. /Macrolide Antibiotics/
Concomitant use of macrolide antibiotics may increase anticoagulant effects; patients taking both anticoagulants and macrolides should have their prothrombin time closely monitored. /Macrolide Antibiotics/
For more complete interaction data (of 8 items) on tilmicosin, please visit the HSDB record page.

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Non-human toxicity values
Oral LD50 of rats (non-fasting males and females) > 2000 mg/kg/bw
Oral LD50 of rats (fasting females) 800 mg/kg/bw
Oral LD50 of rats (fasting males) 850 mg/kg/bw
Subcutaneous LD50 of mice (females) 109 mg/kg/bw
For more complete non-human toxicity data (of 8 items) on tilmicosin, please visit the HSDB record page.

[1]. Micotil 300 New Animal Drug Application.

Tilmicosin is a macrolide antibiotic with the molecular formula C46H80N2O13. It is used to treat respiratory diseases in high-risk cattle susceptible to Mannheimia haemolytica-related respiratory diseases. It has cardiotoxic, antibacterial, and calcium channel blocking effects. It is a macrolide antibiotic, a monosaccharide derivative, and an enone compound.
Tilmicosin is a macrolide antibiotic. In veterinary medicine, it is used to treat respiratory diseases in cattle and sheep caused by Mannheimia haemolytica.
See also: Tilmicosin phosphate (salt form); Tilmicosin; Tilmicosin phosphate (component).

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Mechanism of Action
Tilmicosin has in vitro activity against Gram-positive bacteria and mycoplasma, and is also effective against some Gram-negative bacteria, such as Haemophilus influenzae, hemolytic Mannheimia (Pasteurella), and Pasteurella multocida. However, Manniella species exhibit higher sensitivity to tilmicosin than Pasteurella multocida species. Other tested Gram-negative bacteria, including Enterobacter aerogenes, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella, and Serratia spp., show strong resistance to tilmicosin. Some actinomycete strains also exhibit extremely high resistance to tilmicosin. The antibacterial mechanism of all macrolide antibiotics appears to be the same. They interfere with protein synthesis by reversibly binding to the 50S subunit of the ribosome. They appear to bind to donor sites, thereby preventing the translocation required for peptide chain growth. This effect is primarily limited to rapidly dividing bacteria and mycoplasma. Macrolides are considered bacteriostatic agents… Macrolides show significantly enhanced activity in a higher pH range (7.8–8). /Macrolides/ Macrolides have been reported to modulate host immune and inflammatory responses both in vivo and in vitro. The authors investigated the in vitro effects of two macrolide antibiotics used only in veterinary clinical settings—tilmicosin and tylosin—on the production of nitric oxide (NO), prostaglandin E2 (PGE2), and cytokines in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and mouse peripheral blood mononuclear cells (PBMCs). Compared to 5 μg/mL, concentrations of tilmicosin and tylosin at 10 μg/mL and 20 μg/mL significantly reduced the production of 6-keto-prostaglandin F1α (6-keto-PGF1α), PGE2, NO, tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6, and increased the production of IL-10. Gene expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) was also significantly reduced. These results support the view that macrolide antibiotics may exert their anti-inflammatory effects by regulating the synthesis of various mediators and cytokines involved in the inflammatory process.

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Therapeutic Uses
Veterinary Drugs: Tilmicosin is available in injectable form for the treatment of respiratory diseases in cattle and sheep; it can also be used as a feed premix for the treatment and control of respiratory diseases in pigs.
Therapeutic Category (Veterinary Drugs): Antibacterial
Veterinary Drugs: Macrolide antibiotics are used to treat systemic and local infections. They are generally considered penicillin alternatives for treating streptococcal and staphylococcal infections. Common indications include upper respiratory tract infections, bronchopneumonia, bacterial enteritis, metritis, pyoderma, urinary tract infections, arthritis, etc. Preparations for treating mastitis are also available, with the advantage of a shorter weaning period. /Macrolides/
Drugs (Veterinary Drugs): Tilmicosin is a macrolide antibiotic synthesized from tylosin. Its antibacterial spectrum is similar to tylosin, but it is more active against Pasteurella multocida and hemolytic Pasteurella. Tilmicosin is recommended for the treatment of bacterial pneumonia in calves…
For more complete data on the therapeutic uses of tilmicosin (8 types in total), please visit the HSDB record page.

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Drug Warnings
/VET/: Tilmicosin is not approved for use in female dairy cows aged 20 months and older, veal calves under 1 month of age, or calves fed milk.
Toxicity and side effects of most macrolide antibiotics (except tilmicosin) are uncommon, but pain and swelling may occur at the injection site. Allergic reactions are rare. …Horses are susceptible to gastrointestinal disturbances caused by macrolide antibiotics, which can be severe and even fatal. …Tilmicosin is characterized by cardiotoxicity (tachycardia and decreased contractility). It is contraindicated in pigs and should not be used off-label. Cattle have died after intravenous administration of tilmicosin. Tilmicosin: All species: Tilmicosin should not be administered intravenously to avoid cardiotoxicity. Humans: Injection of tilmicosin may be fatal. Although information on the effects of tilmicosin on humans is limited, susceptibility to cardiotoxicity varies among different species; therefore, caution should be exercised when humans are exposed to tilmicosin, and the cardiovascular system should be closely monitored, especially after accidental injection. Immediate veterinary attention should be sought after accidental injection. Dogs: Tachycardia and decreased myocardial contractility have been observed after tilmicosin injection in experimental dogs. Goats: Intramuscular or subcutaneous injection of tilmicosin exceeding 10 mg/kg body weight may cause poisoning in goats. Horses: Intramuscular or subcutaneous injection of tilmicosin exceeding 10 mg/kg body weight may cause poisoning in horses. Pigs: Injection of tilmicosin into pigs may be fatal due to cardiovascular toxicity. Treatment with adrenaline for cardiovascular toxicity caused by intravenous tilmicosin increases the risk of death. /Veterinarian:/ In cattle, tilmicosin distributes into milk at effective antimicrobial concentrations against susceptible pathogens, but detectable concentrations can persist for weeks (up to 42 days). Due to the excessively long withdrawal period, tilmicosin should not be administered to lactating cows.

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.)