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.
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.
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.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
相互作用
在家禽中，泰妙菌素会干扰莫能菌素和盐霉素的代谢，如果这些药物同时使用，它们会变得有毒。
In poultry, tiamulin interferes with monensin and salinomycin metabolism, and if the drugs are fed together, they become toxic.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
它很容易从肠道吸收，在服药后30分钟内就可以在血液中找到。
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.
A compound selected from 14-O-[((Alkyl-, cycloalkyl-, heterocycloalkyl-, heteoroaryl-, or aryl)-sulfanyl)-acetyl]-12-epi-mutilins, or 14-O-[((Alkyl-, cycloalkyl-, heterocycloalkyl-, heteoroaryl-, or aryl)-oxy)-acetyl]-12-epi-mutilins, wherein 12-epi-mutilin is characterized in that the mutilin ring at position 12 is substituted by two substituents, the first substituent at position 12 of the mutilin ring is a methyl group which methyl group has the inverse stereochemistry compared with the stereochemistry of the methyl group at position 12 of the naturally occurring pleuromutilin ring, the second substituent at position 12 of the mutilin ring is a hydrocarbon group comprising at least one nitrogen atom and all other substituents of the mutilin ring having the same stereochemistry compared with the stereochemistry of the substituents at the corresponding positions in the naturally occurring pleuromutilin ring; optionally in the form of a salt and/or solvate, wherein the naturally occurring pleuromutilin is of formula
processes for the preparation of such compounds and their use as pharmaceuticals.
[EN] THERAPEUTIC USE OF PLEUROMUTILINS<br/>[FR] UTILISATION THÉRAPEUTIQUE DE PLEUROMUTILINES
申请人：NABRIVA THERAPEUTICS GMBH
公开号：WO2021209596A1
公开（公告）日：2021-10-21
A compound selected from 14-O-[((Alkyl-, cycloalkyl-, heterocycloalkyl-, heteroraryl-, or aryl)-sulfanyl)-acetyl]-12-epi-mutilins, or 14-O-[((Alkyl-, cycloalkyl-, heterocycloalkyl-, heteroaryl-, or aryl)-oxy)-acetyl]-12-epi-mutilins, wherein 12-epi-mutilin is characterized in that the mutilin ring at position 12 is substituted by two substituents, the first substituent at position 12 of the mutilin ring is a methyl group which methyl group has the inverse stereochemistry compared with the stereochemistry of the methyl group at position 12 of the naturally occurring pleuromutilin ring, the second substituent at position 12 of the mutilin ring is a hydrocarbon group comprising at least one nitrogen atom and all other substituents of the mutilin ring having the same stereochemistry compared with the stereochemistry of the substituents at the corresponding positions in the naturally occurring pleuromutilin ring; optionally in the form of a pharmaceutically acceptable salt and/or solvate, prodrug or metabolite, wherein the naturally occurring pleuromutilin is of formula (I) for the specific use in the treatment or prevention of a disease mediated by a virus. The invention further relates to 12-epi-12-desvinyl-14-O-[(Piperidin-4-ylsulfanyl]-acetyl]-12- [2-(3-methyl-pyrazin-2-yl)-ethenyl]-mutilin and its therapeutic uses.
