Macrolide

Telithromycin (HMR3647) (0-50 μg/mL, 30 min) inhibits the production of MUC5AC induced by C. pneumoniae.The NF-kB activation caused by C. pneumoniae is suppressed by telithromycin (0-50 μg/mL, 30 min)[1].
LPS-stimulated RAW 264.7 macrophages produce less MIP-2 and TNF-α when exposed to telithromycin (10 mg/mL, 1 h) in a dose-dependent manner.Telithromycin (10 mg/mL, 1 h) reduces the LPS-induced neutrophil influx in BAL fluid, increases apoptosis in cells, and inhibits NF-kB activation[2].

In the BAL fluid of animals nebulized with LPS, telithromycin (HMR3647) (20 mg/kg, ip., single) decreases the levels of protein, nitrite, MIP-2, and TNF-α[2].

MUC5AC production in bronchial epithelial cells after stimulation with C. pneumoniae was analyzed by ELISA and quantitative RT-PCR. NF-kappaB and phosphorylated ERK were also analyzed. For inhibition study, cells were pretreated with azithromycin, clarithromycin and telithromycin before stimulation.[1]
C. pneumoniae dose-dependently induced MUC5AC production and gene expression. The ERK-NF-kappaB pathway was involved in C. pneumoniae-induced MUC5AC production. Macrolides and ketolides dose-dependently reduced C. pneumoniae-induced MUC5AC production. However, azithromycin was apparently less effective than the other antibiotics. Clarithromycin and telithromycin, but not azithromycin, reduced NF-kappaB activation.[1]

We measured the effects of TEL on the response of RAW 264.7 macrophages to LPS and of murine lung epithelial (MLE)-12 cells to supernatants of LPS-stimulated RAW 264.7 macrophages. Macrophage inflammatory protein (MIP)-2 and tumor necrosis factor (TNF)-alpha production, nuclear factor (NF)-kappaB activation, and apoptosis were determined. Acute airway inflammation was induced in untreated and TEL-treated BALB/c mice by nebulization with LPS. Total number of leukocytes, macrophages, and neutrophils, the protein concentration, and nitrite and cytokine levels were determined in the BAL fluid.[2]
TEL inhibited in a dose-dependent manner the production of MIP-2 and TNF-alpha by LPS-stimulated RAW 264.7 macrophages, and the production of MIP-2 by MLE-12 epithelial cells to supernatants of LPS-stimulated RAW 264.7 macrophages. NF-kappaB activation was inhibited and apoptosis was increased in both cell lines by TEL. The LPS-induced influx of neutrophils in BAL fluid was decreased by TEL pretreatment. [2]

Animal Model: LPS-Nebulized Mice[2]
Dosage: 20 mg/kg
Administration: 20 mg/kg, ip., single
Result: induced significant reductions in MIP-2 levels, decreased TNF-α and nitrite concentrations, and increased protein concentration.

Absorption, Distribution and Excretion
Absolute bioavailability is approximately 57%. Maximum concentrations are reached 0.5 to 4 hours after oral administration. Food intake does not affect absorption. Systemically available telithromycin is eliminated via multiple routes: 7% of the dose is excreted unchanged in feces via bile and/or intestinal secretions; 13% of the dose is excreted unchanged in urine via the kidneys; and 37% of the dose is metabolized by the liver. 2.9 L/kg Telithromycin concentrations in leukocytes are higher than in plasma, and clearance from leukocytes is slower than clearance from plasma. The mean leukocyte concentration of telithromycin peaks at 72.1 μg/mL 6 hours after administration and remains at 14.1 μg/mL 24 hours after 5 consecutive days of 600 mg once daily. After 10 consecutive days of 600 mg once daily, the leukocyte concentration remains at 8.9 μg/mL 48 hours after the last dose.
The volume of distribution after intravenous infusion is 2.9 L/kg. Telithromycin is widely distributed throughout the body. Telithromycin is secreted into rat milk.
Absorption is rapid, with an absolute bioavailability of 57% in both young and elderly patients. Food does not affect the rate or extent of absorption. The AUC after a single dose is 8.25 μg h/mL, and the AUC after multiple doses is 12.5 μg h/mL.
Systemically available telithromycin is eliminated via multiple routes, specifically: 7% of the dose is excreted unchanged in feces via bile and/or intestinal secretions; 13% of the dose is excreted unchanged in urine via the kidneys; and 37% of the dose is metabolized in the liver.
For more complete data on the absorption, distribution, and excretion of telithromycin (11 in total), please visit the HSDB record page.

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Metabolism/Metabolites
Hepatic - Estimated 50% is metabolized by CYP3A4, and 50% is not metabolized by cytochrome P450.
Approximately 70% of the oral dose (33% first-pass metabolism, 37% systemic metabolism) is metabolized approximately equal in amount by cytochrome P450 (CYP)3A4 and non-CYP3A4 isoenzymes to four major metabolites. Systemically available telithromycin is primarily excreted unchanged in feces (7%), unchanged in urine (13%), and the remaining 37% is metabolized in the liver.
Biotransformation: Hepatic metabolism; 37% of the dose is metabolized in the liver. Metabolism accounts for approximately 70% of the dose. The major metabolites account for 12.6% of the AUC, while the other three quantitative metabolites account for 3% or less of the telithromycin AUC.
In summary, metabolism accounts for approximately 70% of the dose. In plasma, following administration of an 800 mg radiolabeled dose, the parent compound was the major circulating compound, accounting for 56.7% of the total radioactivity. The major metabolite accounted for 12.6% of the telithromycin AUC. Three other plasma metabolites were quantified, each accounting for 3% or less of the telithromycin AUC. It is estimated that approximately 50% of its metabolism is mediated by CYP 450 3A4, and the remaining 50% is independent of CYP 450.

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Biological Half-Life
Major elimination half-life is 2–3 hours; terminal elimination half-life is 10 hours.
Elimination: 10 hours after oral administration.

Hepatotoxicity
Like other macrolide antibiotics, telithromycin is associated with a low incidence (1% to 2%) of transient serum enzyme elevations during treatment. However, these elevations are usually transient and return to normal with continued use, and similar rates of serum enzyme elevations can occur with control drugs. More importantly, telithromycin has been associated with severe, acute, clinically significant hepatotoxicity, first reported shortly after its widespread approval in the United States. The latency period for liver injury is usually short, with some cases developing symptoms within one or two days of starting treatment; the average latency period is one week. Liver injury typically has a rapid onset, accompanied by fatigue, weakness, jaundice, and fever. The pattern of enzyme elevation is usually hepatocellular, and serum transaminase levels can be very high (>1000 U/L). While telithromycin has been reported to cause mild or non-jaundiced liver injury, some cases have been very severe, with rapid progression of liver failure, ascites, and hepatic encephalopathy. Eosinophilia and rash may also occur, but are not common. There have been reports of recurrence of injury after re-exposure. Probability score: A (Known cause of clinically significant liver injury). Effects during pregnancy and lactation: ◉ Overview of use during lactation: Since there is no published experience regarding the use of telithromycin during lactation, alternative medications may be preferred, especially in breastfed newborns or preterm infants. ◉ Effects on breastfed infants: No relevant published information found as of the revision date. ◉ Effects on lactation and breast milk: No relevant published information found as of the revision date. Protein binding: 60-70% Primarily binds to human serum albumin. Interactions: Telithromycin is contraindicated with pimozide; risk of elevated pimozide blood concentrations.
Concomitant use of telithromycin with phenobarbital, phenytoin, or St. John's wort may result in telithromycin plasma concentrations below therapeutic levels, thus reducing efficacy.
Concomitant use of telithromycin with benzodiazepines that are metabolized by CYP3A4 and have a high first-pass effect may increase the plasma concentrations of other benzodiazepines.
Concomitant use of midazolam with telithromycin may increase the AUC; patients should be monitored, and the midazolam dose adjusted as necessary.
For more complete data on drug interactions (20 in total) of telithromycin, please visit the HSDB record page.

[1]. Azithromycin, clarithromycin and telithromycin inhibit MUC5AC induction by Chlamydophila pneumoniae in airway epithelial cells. Pulm Pharmacol Ther. 2009 Dec;22(6):580-6.

[2]. Effects of telithromycin in in vitro and in vivo models of lipopolysaccharide-induced airway inflammation. Chest. 2008 Jul;134(1):20-9.

Therapeutic Uses

Antibacterial Use>
Telexycin is indicated for the treatment of acute bacterial exacerbations of chronic bronchitis caused by Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis. /Included on US product label/
Telexycin is indicated for the treatment of group A beta-hemolytic streptococcal infections as an alternative therapy when beta-lactam antibiotics are unavailable. /Not included on US product label/
Telexycin is indicated for the treatment of community-acquired pneumonia caused by Streptococcus pneumoniae (including multidrug-resistant strains), Haemophilus influenzae, Chlamydia pneumoniae, Mycoplasma pneumoniae, or Moraxella catarrhalis. /Not included on US product label/
Telexycin is indicated for the treatment of acute bacterial sinusitis caused by Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, or Staphylococcus aureus. /Included on US product label/
Drug Warnings

Pseudomembranous colitis has been reported with almost all antibacterial drugs (including telexycin), ranging in severity from mild to life-threatening. Therefore, pseudomembranous colitis should be considered in patients who experience diarrhea after taking any antibiotic. FDA Pregnancy Risk Category: C / Risk cannot be ruled out. There is a lack of adequate, well-controlled human studies, and animal studies have not shown any risk to the fetus or lack relevant data. There is a possibility of fetal harm if this medication is taken during pregnancy; however, the potential benefit may outweigh the potential risk. / Treatment with anti-infective drugs, including telithromycin, may lead to Clostridium difficile overgrowth. If diarrhea occurs, Clostridium difficile-associated diarrhea and colitis (antibiotic-associated pseudomembranous colitis) should be considered and treated accordingly. Some mild cases of Clostridium difficile-associated diarrhea and colitis may resolve simply by discontinuing the medication. Moderate to severe cases can be treated with fluid, electrolyte, and protein supplementation; if colitis is severe, appropriate anti-infective treatment (e.g., oral metronidazole or vancomycin) is recommended. To reduce the development of drug-resistant bacteria and maintain the efficacy of telithromycin and other antibiotics, use only to treat infections confirmed or highly suspected to be caused by susceptible bacteria. When selecting or adjusting anti-infective therapy regimens, the results of bacterial culture and in vitro drug susceptibility testing should be considered. In the absence of such data, when selecting anti-infective drugs for empirical treatment, local epidemiology and resistance patterns should be taken into account. For more complete data on drug warnings for telithromycin (14 in total), please visit the HSDB records page.

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Pharmacodynamics
Telithromycin is a ketolactone antibiotic with an antibacterial spectrum similar to or slightly broader than penicillin. It is commonly used in patients allergic to penicillin. For respiratory infections, it provides better coverage against atypical pathogens, including mycoplasma. Telithromycin inhibits bacterial growth by binding to the bacterial 50S ribosomal subunit, interfering with the translocation and elongation of bacterial peptides.

C43H65N5O10

812.003700000001

811.473

C, 63.60; H, 8.07; N, 8.62; O, 19.70

191114-48-4

3002190

White to off-white solid powder

1.3±0.1 g/cm3

966.2±65.0 °C at 760 mmHg

176-188ºC

538.2±34.3 °C

0.0±0.3 mmHg at 25°C

1.589

4.52

1

13

11

58

1440

13

O[C@H]1[C@]([H])(O[C@@H]([C@](C)(OC)C[C@@H](C)C2=O)[C@@H](C)C([C@@H](C)C(O[C@H](CC)[C@](OC(N3CCCCN4C=C(C5=CC=CN=C5)N=C4)=O)(C)[C@@]3([H])[C@H]2C)=O)=O)O[C@H](C)C[C@@H]1N(C)C

LJVAJPDWBABPEJ-PNUFFHFMSA-N

InChI=1S/C43H65N5O10/c1-12-33-43(8)37(48(41(53)58-43)19-14-13-18-47-23-31(45-24-47)30-16-15-17-44-22-30)27(4)34(49)25(2)21-42(7,54-11)38(28(5)35(50)29(6)39(52)56-33)57-40-36(51)32(46(9)10)20-26(3)55-40/h15-17,22-29,32-33,36-38,40,51H,12-14,18-21H2,1-11H3/t25-,26-,27+,28+,29-,32+,33-,36-,37-,38-,40+,42-,43-/m1/s1

(3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-10-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-11-methoxy-3a,7,9,11,13,15-hexamethyl-1-(4-(4-(pyridin-3-yl)-1H-imidazol-1-yl)butyl)octahydro-2H-[1]oxacyclotetradecino[4,3-d]oxazole-2,6,8,14(1H,7H,9H)-tetraone

HMR3647; RU-66647; RU 66647; RU66647;HMR-3647; HMR 3647;

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 (~123.15 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (3.08 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 (3.08 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 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 (3.08 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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Solubility in Formulation 4: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.5 mg/mL (3.08 mM)

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