Tiamulin (SQ-14055; SQ14055; SQ14055) is a novel and potent pleuromutilin antibiotic that has been used in veterinary medicine in particularly for pigs and poultry. Tiamulin is active against gram-positive bacteria, mycoplasmas, and anaerobes, including Brachyspira hyodysenteriae.
Physicochemical Properties
| Molecular Formula | C28H47NO4S |
| Molecular Weight | 493.7421 |
| Exact Mass | 493.322 |
| Elemental Analysis | C, 68.11; H, 9.60; N, 2.84; O, 12.96; S, 6.49 |
| CAS # | 55297-95-5 |
| Related CAS # | Tiamulin fumarate;55297-96-6 |
| PubChem CID | 656958 |
| Appearance | Sticky, translucent yellowish mass |
| Density | 1.1±0.1 g/cm3 |
| Boiling Point | 563.0±50.0 °C at 760 mmHg |
| Melting Point | 147-148ºC |
| Flash Point | 294.3±30.1 °C |
| Vapour Pressure | 0.0±3.5 mmHg at 25°C |
| Index of Refraction | 1.541 |
| LogP | 5.93 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 6 |
| Rotatable Bond Count | 10 |
| Heavy Atom Count | 34 |
| Complexity | 770 |
| Defined Atom Stereocenter Count | 8 |
| SMILES | S(C([H])([H])C([H])([H])N(C([H])([H])C([H])([H])[H])C([H])([H])C([H])([H])[H])C([H])([H])C(=O)O[C@]1([H])C([H])([H])[C@](C([H])=C([H])[H])(C([H])([H])[H])[C@]([H])([C@]([H])(C([H])([H])[H])[C@]23C([H])([H])C([H])([H])C([C@@]2([H])C1(C([H])([H])[H])C([H])(C([H])([H])[H])C([H])([H])C3([H])[H])=O)O[H] |
| InChi Key | UURAUHCOJAIIRQ-KWVPEQCVSA-N |
| InChi Code | InChI=1S/C28H47NO4S/c1-8-26(6)17-22(33-23(31)18-34-16-15-29(9-2)10-3)27(7)19(4)11-13-28(20(5)25(26)32)14-12-21(30)24(27)28/h8,19-20,22,24-25,32H,1,9-18H2,2-7H3/t19-,20+,22-,24+,25+,26-,27-,28+/m1/s1 |
| Chemical Name | (3aS,4R,5S,6S,8R,9S,9aR,10R)-2-[[2-(Diethylamino)ethyl]thio]acetic Acid 6-Ethenyldecahydro-5-hydroxy-4,6,9,10-tetramethyl-1-oxo-3a,9-propano-3aH-cyclopentacycloocten-8-yl Ester |
| Synonyms | SQ 14055; SQ-14055; SQ14055; Tiamulin; |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| ln Vitro | Tiamulin, a semi-synthetic derivative of the diterpenoid antibiotic truncated pleuromutilin, has been found to be efficacious in the investigation of mycoplasma-primarily induced neck inflammation [1]. Tiamulin is Gram Active against positive bacteria (Staphylococcus, Streptococcus, Clostridium, Mysterella), spirochetes (Brachyspira porcine diarrhea, Brachyspira asexual, Brachyspira pilosa, and Brachyspira intermedius), and mycoplasma strains (Mycoplasma gallisepticum, Mycoplasma synoviae, M. meleagridis, and M. iowae) [1]. However, tiamulin has reduced activity against Gram-negative bacteria (Pasteurella, Klebsiella, Haemophilus, Clostridium, Campylobacter, Bacteroidetes) [1]. In order to allow peptidase and subsequent protein synthesis, tRNA must be properly positioned for CCA termination of the tRNA, which is hindered by titimulin's binding to rRNA in the ribosomal peptidyltransferase groove [1]. |
| ln Vivo | Treatment of poultry-destroying spirocheteosis in breeders and eggs with tiamulin (25 mg/kg for 5 days) proved to be highly successful in tests using fake infections with Bacillus trichocystis and Bacillus intermedius [1]. |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion It is readily absorbed from the gut and can be found in the blood within 30 minutes after dosing. Tiamulin is well absorbed orally by swine. Approximately 85% of a dose is absorbed and peak levels occur between 2-4 hours after a single oral dose. Tiamulin is apparently well distributed, with highest levels found in the lungs. In pigs (2 animals per sex and group), following oral administration of 5 mg (14)C-tiamulin base/kg bw/day for 10 consecutive days, approximately 35% of the dose was eliminated in urine and 65% in feces. The total residue concentrations in liver, kidney, muscle and fat were 21,880, 600, 720 and 720 ug equivalents/kg, respectively, 10 days after dosing and 480, 220, 430, 910 ug equivalents/kg after 25 days. Metabolism / Metabolites In laying hens, broilers and turkeys (6 animals per group) orally dosed with 10 mg (3)H-tiamulin hydrogen fumarate/kg bw/day for 5 consecutive days, over 15 metabolites were detected in tissue extracts but most of the residue was accounted for by 4 metabolites. No individual metabolite represented more than 30% of the total residue in poultry tissues. In the liver of pigs orally treated with tiamulin, the percentage of the metabolites that can be hydrolyzed to 8-alpha-hydroxymutilin (ie marker residue) to total residues was 3.5, 3.6 and 5.7% at 4, 24 and 96 hours after treatment, respectively. In pigs (4 animals per sex and group) given ad libitum access to feed containing tiamulin at a concentration of 39 mg/kg for 10 consecutive days, the average concentrations of metabolites in liver that could be hydrolyzed to form 8-alpha-hydroxymutilin, as detected by gas chromatography with electrochemical detection, were 447 and 247 ug equivalent/kg at 2 and 12 hours after dosing, respectively. In animals does for 18 consecutive days, the average concentrations of 8-alpha-hydroxymutilin in liver were 184, 256, 214 and 175 ug equivalents/kg at 12, 16, 20 and 24 hours after dosing, respectively. In pigs orally dosed with (3)H-tiamulin, 6-desmethyltiamulin accounted for less than 1% of the total residue in bile and urine samples and had 67% of the antimicrobiological activity of tiamulin when tested by agar plate diffusion. Four other metabolites were found to have antimicrobiological activities relative to tiamulin of between 0.7 and 3.3% and all other metabolites had relative activities of less than 0.3%. Tiamulin is extensively metabolized to over 20 metabolites, some having antibacterial activity. Approximately 30% of these metabolites are excreted in the urine with the remainder excreted in the feces. |
| Toxicity/Toxicokinetics |
Toxicity Summary IDENTIFICATION AND USE: Tiamulin, when administered in the drinking water for five consecutive days, is an effective antibiotic for the treatment of swine dysentery associated with Brachyspira (formerly Serpulina or Treponema) and for treatment of swine pneumonia due to Actinobacillus pleuropneumoniae. As a feed additive, it is used to cause increased weight gain in swine. HUMAN EXPOSURE AND TOXICITY: Topical administration of a 0.05% formulation of tiamulin did not cause skin irritation or sensitization. Another study was carried out in 6 healthy male human volunteers. Three volunteers were given 5 oral doses progressing from 0.125 to 7.2 mg/kg bw with 72 hours between each dose. The remaining volunteers were given a single oral dose in the range of 8.2 to 10.7 mg/kg bw tiamulin. There was no substance-related changes in blood pressure, serum chemistry or electrocardiograms. ANIMAL STUDIES: Overdoses of tiamulin have produced transitory salivation, vomiting and an apparent calming effect on the pig. In a subchronic study, rats were fed diets containing 0.5 or 30 mg tiamulin/kg bw/day for 26 weeks. Further groups of rats received 180 mg/kg bw/day for 10 weeks, followed by 270 mg/kg bw/day for 16 weeks; one group was necropsied at the end of treatment, the remaining rats were maintained on untreated control diets for a further 4 or 8 weeks. There were increases in serum cholesterol and in water intake in the 180 mg/kg bw group. When the dose was increased to 270 mg/kg bw/day, the effects included increased serum alkaline phosphatase, alanine phosphatase, alanine aminotransferase and aspartate aminotransferase. Abdominal distension, dense feces and increased urine specific gravity were also observed. Absolute and relative liver weights were increased in both sexes and fatty infiltration of the liver was observed on histopathological examination. In a chronic study, dogs were given daily oral doses of 0, 3, 10 or 30 mg/kg bw/day of tiamulin for 54 weeks. In the groups given 10 and 30 mg/kg bw/day, occasional emesis was observed, serum potassium concentrations were decreased and electrocardiograms showed prolongation of the QT interval. Serum lactate dehydrogenase (LDH) was significantly increased; there was no increase in the cardiac-related isoenzyme LDH1. Rats were fed diets containing tiamulin at concentrations designed to provide intakes of 0, 2, 8 or 32 mg/kg bw/day of tiamulin for 30 months. There was no significant dose-related trend in the incidence of any tumor type. In another study, mice were fed diets containing the equivalent of 0, 1, 6 or 48 mg/kg bw/day of tiamulin for up to 123 weeks. There was no significant dose-related trend in the incidence of any tumor type. Pregnant female rats were given daily oral doses of 0, 30, 100 or 300 mg/kg bw/day from days 6 to 15 of gestation. At 300 mg/kg bw/day there were minor signs of maternal toxicity. At this dose level, the mean fetal weight was reduced and there was an increased incidence of retarded skeletal development. There was no evidence of teratogenicity. Pregnant female rabbits were given daily oral doses of 0, 30, 55 or 100 mg/kg bw/day from days 6 to 18 of gestation. Doses of 55 mg/kg bw/day and above caused the deaths of some dams and maternal body weight gain was reduced. Litter size and fetal weights were reduced at 55 mg/kg bw/day and above. There was no evidence of teratogenicity at any dose level. Several reproductive studies were performed in pigs. Breeding sows were fed a diet containing 200 mg/kg feed from days 84 to 92 of gestation, another group was maintained on a diet containing 16 mg/kg bw/day from 2 days after mating for 6 weeks, and further groups were given tiamulin in the drinking water at a dose of 8.8 mg/kg bw/day for various periods during gestation and in some cases up to weaning of the offspring. There were no adverse effects on health of the sows, pregnancy, parturition, letter size, growth and survival of the piglets, estrus cycle or subsequent breeding performance. When given to breeding boars, at a diet containing 16 mg/kg bw/day for 14 days, there were no effects on health status, libido or semen quality. Tiamulin did not induce gene mutations in Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 or TA1538. An in vitro assay for gene mutation at the HPRT locus of V79 Chinese hamster cells also gave negative results. In an in vivo micronucleus test in mice tiamulin had no effect on the frequency of micronucleated polychromatic erythrocytes. Interactions The characteristics of the toxic interaction between monensin & tiamulin were investigated in rats. A three-day comparative oral repeated-dose toxicity study was performed in Phase I, when the effects of monensin & tiamulin were studied separately (monensin 10, 30, & 50 mg/kg or tiamulin 40, 120, & 200 mg/kg body weight, respectively). In Phase II, the two compounds were administered simultaneously to study the toxic interaction (monensin 10 mg/kg & tiamulin 40 mg/kg b.w., respectively). Monensin proved to be toxic to rats at doses of 30 & 50 mg/kg. Tiamulin was well tolerated up to the dose of 200 mg/kg. After combined admin, signs of toxicity were seen (including lethality in females). Monensin caused a dose-dependent cardiotoxic effect & vacuolar degeneration of the skeletal muscles in the animals given 50 mg/kg. Both compounds exerted a toxic effect on the liver in high doses. After simultaneous admin of the two compounds, there was a mild effect on the liver (females only), hydropic degeneration of the myocardium & vacuolar degeneration of the skeletal muscles. The alteration seen in the skeletal muscles was more marked than that seen after the admin of 50 mg/kg monensin alone. Studies were carried out to investigate the effects of monensin & tiamulin, & the simultaneous admin of both compounds on microsomal enzymes in rats. In Phase I of the experiments the effects of monensin & tiamulin were studied separately (monensin 10, 30, & 50 mg/kg or tiamulin 40, 120, & 200 mg/kg body weight, respectively), while in Phase II the two compounds were administered simultaneously (monesin 10 mg/kg & tiamulin 40 mg/kg b.w., respectively). When monensin was administered by itself, it exerted no significant effect on microsomal liver enzymes. In a few cases, slight inhibition of certain enzyme activities was seen. Tiamulin provoked a dose-dependent hepatic enzyme induction. The combined admin of monensin & tiamulin at low doses (10 & 40 mg/kg, respectively) resulted in marked elevation of P450-related enzyme activities. The enzyme induction was more pronounced in females than in males. The results suggest that the simultaneous admin of tiamulin may influence the biotransformation of monensin, possibly increasing the amount of reactive metabolite(s) of the ionophore antibiotic. Tiamulin is an antibiotic frequently used in veterinary medicine. The drug has been shown to produce clinically important interactions with other compounds that are administered simultaneously. An NIH/3T3 cell line, stably expressing human cytochrome P450 (EC 1.14.14.1) cDNA (CYP3A4), was used to study the effect of tiamulin on CYP3A4 activity. The 6 beta-hydroxylation activity of testosterone, which is increased in CYP3A4-expressing cells compared to vector-transfected cells, showed reduced activity after incubation with 1 microM tiamulin and was completely reduced to background level after incubation with 2, 5 and 10 microM tiamulin. The CYP3A4-expressing cell line was used in combination with a shuttle vector containing the bacterial lacZ' gene to study the effect of tiamulin on CYP3A4-mediated mutagenicity of aflatoxin B1. The mutation frequency of aflatoxin B1 could be completely inhibited by tiamulin in CYP3A4-expressing cells, but no effect was observed on the mutation frequency of the direct mutagen ethylmethanesulphonate. Western blotting of homogenates of the CYP3A4-expressing cell line showed stabilization of CYP3A4 protein after incubation with tiamulin, supporting the hypothesis that the mechanism of inhibition is by binding of tiamulin to the cytochrome. In poultry, tiamulin interferes with monensin and salinomycin metabolism, and if the drugs are fed together, they become toxic. For more Interactions (Complete) data for TIAMULIN (10 total), please visit the HSDB record page. Non-Human Toxicity Values LD50 Rat oral 2230 mg/kg LD50 Rat sc 4380 mg/kg LD50 Rat iv 20 mg/kg LD50 Mouse oral 710 mg/kg For more Non-Human Toxicity Values (Complete) data for TIAMULIN (15 total), please visit the HSDB record page. |
| References | [1]. Islam KM, et al. The activity and compatibility of the antibiotic tiamulin with other drugs in poultry medicine--A review. Poult Sci. 2009 Nov;88(11):2353-9. |
| Additional Infomation |
Tiamulin is a carbotricyclic compound that is pleuromutilin in which the hydroxyacetate group is replaced by a 2-{[2-(diethylamino)ethyl]sulfanyl}acetate group. An antibacterial drug, tiamulin is used in veterinary medicine (generally as its hydrogen fumarate salt) for the treatment of swine dysentery caused by Serpulina hyodysenteriae. It has a role as an antibacterial drug. It is a carbotricyclic compound, a carboxylic ester, a cyclic ketone, a tertiary amino compound, a secondary alcohol, an organic sulfide, a tetracyclic diterpenoid and a semisynthetic derivative. It is functionally related to a Pleuromutilin. Tiamulin is a pleuromutilin antibiotic drug that is used in veterinary medicine particularly for pigs and poultry. See also: Tiamulin Fumarate (has salt form); Chlortetracycline; Tiamulin (component of). Mechanism of Action The mutation frequency of aflatoxin B1 could be completely inhibited by tiamulin in CYP3A4-expressing cells, but no effect was observed on the mutation frequency of the direct mutagen ethylmethanesulphonate. Western blotting of homogenates of the CYP3A4-expressing cell line showed stabilization of CYP3A4 protein after incubation with tiamulin, supporting the hypothesis that the mechanism of inhibition is by binding of tiamulin to the cytochrome. Tiamulin is a semisynthetic diterpene antibiotic frequently used in farm animals. The drug has been shown to produce clinically important--often lethal--interactions with other compounds. It has been suggested that this is caused by a selective inhibition of oxidative drug metabolism via the formation of a cytochrome P-450 metabolic intermediate complex. In the present study, rats were treated orally for 6 days with tiamulin at two different doses: 40 & 226 mg/kg of body weight. For comparison, another group received 300 mg of triacetyloleandomycin (TAO) per kg, which is equivalent to the 226-mg/kg tiamulin group. Subsequently, microsomal P-450 contents, P-450 enzyme activities, metabolic intermediate complex spectra, & P-450 apoprotein concentrations were assessed. In addition, effects on individual microsomal P-450 activities were studied in control microsomes at different tiamulin & substrate concentrations. In the rats treated with tiamulin, a dose-dependent complex formation as evidenced by its absorption spectrum & an increase in cytochrome P-4503A1/2 contents as assessed by Western blotting (immunoblotting) were found. The effects were comparable to those of TAO. Tiamulin induced microsomal P-450 content, testosterone 6 beta-hydroxylation rate, erythromycin N-demethylation rate, & the ethoxyresorufin O-deethylation activity. Other activities were not affected or decreased. When tiamulin was added to microsomes of control rats, the testosterone 6 beta-hydroxylation rate & the erythromycin N-demethylation were strongly inhibited. It is concluded that tiamulin is a potent & selective inducer-inhibitor of cytochrome P-450. Though not belonging to the macrolides, the compound produces an effect on P-450 similar to those of TAO & related compounds. Therapeutic Uses Anti-Bacterial Agents MEDICATION (VET): Denagard (tiamulin), when administered in the drinking water for five consecutive days, is an effective antibiotic for the treatment of swine dysentery associated with Brachyspira (formerly Serpulina or Treponema) hyodysenteriae susceptible to tiamulin at a dose level of 3.5 mg tiamulin hydrogen fumarate per pound of body weight daily and for treatment of swine pneumonia due to Actinobacillus pleuropneumoniae susceptible to tiamulin when given at 10.5 mg tiamulin hydrogen fumarate per pound of body weight daily. /Included in US product label/ MEDICATION (VET): Tiamulin is a diterpenic veterinary drug widely used in swine for the control of infectious diseases, including swine dysentery & enzootic pneumonia. MEDICATION (VET): In veterinary medicine, tiamulin is used for treatment and prophylaxis of dysentery, pneumonia and mycoplasmal infections in pigs and poultry. Drug Warnings For use in animals only - Not for human use. Swine being treated with Denagard (tiamulin) should not have access to feeds containing polyether ionophores (e.g., monensin, lasalocid, narasin, salinomycin and semduramicin) as adverse reactions may occur. Adverse effects occurring with this drug at usual doses are considered unlikely. Rarely, redness of the skin, primarily over the ham and underline, has been observed. It is recommended to discontinue the medication, provide clean drinking water, and hose down the area or move affected animals to clean pens. In poultry, tiamulin interferes with monensin and salinomycin metabolism, and if the drugs are fed together, they become toxic. Swine being treated with Denagard (tiamulin) should not have access to feeds containing polyether ionophores (e.g., monensin, lasalocid, narasin, salinomycin and semduramicin) as adverse reactions may occur. |
Solubility Data
| Solubility (In Vitro) |
DMSO : ~98 mg/mL ( ~198.48 mM ) Water : ~98 mg/mL Ethanol : ~98 mg/mL |
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples. Injection Formulations (e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] *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. Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline) Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline) Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline) Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil) Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Oral Formulations Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). Oral Formulation 3: Dissolved in PEG400 Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose Oral Formulation 6: Mixing with food powders Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0254 mL | 10.1268 mL | 20.2536 mL | |
| 5 mM | 0.4051 mL | 2.0254 mL | 4.0507 mL | |
| 10 mM | 0.2025 mL | 1.0127 mL | 2.0254 mL |