Macrolide antibiotic

P. falciparum cannot grow when erythromycin is present; its IC50 and IC90 values are 58.2 μM and 104.0 μM, respectively[1].
Erythromycin (10 μM, 100 μM; 24 h, 72 h) exhibits anti-inflammatory and antioxidant properties. It also suppresses the accumulation of 4-HNE (p<0.01) and 8-OHdG (p<0.01) and significantly lowers the expression of TNF-α (p<0.01) and Iba-1 (p<0.01)[4].

Erythromycin (gastric intubation; 0.1–50 mg/kg; 30-120 days) slows the growth of tumors and increases the amount of time that mice survive after receiving a dose of 5 mg/kg.When given at a dose of 50 mg/kg, erythromycin (gastric intubation; 5 mg/kg) shortens the mean survival time in tumor-bearing mice by 4-5 days. However, it protects mice alive even 120 days after inoculation.[3]. A single injection of erythromycin (i.h.; 50 mg/kg) protects against cerebral ischemia reperfusion injury in a rat model[4].

Erythromycin inhibited growth of P. falciparum with IC50 and IC90 values of 58.2+/-7.7 microM and 104.0+/-10.8 microM, respectively. The activity of antimalarial drugs in combination with azithromycin or erythromycin against P. falciparum K1 were compared. Combinations of chloroquine with azithromycin or erythromycin showed synergistic effects against parasite growth in vitro. Combinations of quinine-azithromycin and quinine-erythromycin showed potentiation. Additive effects were observed in mefloquine-azithromycin and mefloquine-erythromycin combinations. Similar results were also produced by pyronaridine in combination with azithromycin or erythromycin. However, artesunate-azithromycin and artesunate-erythromycin combinations had antagonistic effects. The in vitro data suggest that azithromycin and erythromycin will have clinical utility in combination with chloroquine and quinine. The worldwide spread of chloroquine-resistant P. falciparum might inhibit the ability to treat malaria patients with chloroquine-azithromycin and chloroquine-erythromycin in areas of drug-resistant. The best drug combinations against multidrug-resistant P. falciparum are quinine-azithromycin and quinine-erythromycin [4].

Cell Line: Primary cortical neuron of embryos (derived from the cerebral cortices of Sprague-Dawley rats 17 days old)
Concentration: 10, 100 μM
Incubation Time: 24, 72 hours
Result: increased the cultivated neuronal cells' viability in vitro following three hours of oxygen-glucose deprivation (OGD).

Animal Model: Six-week-old female ddY mice with EAC cellsor six-week-old CDF mice with P388 cells[3] Dosage: 0.1 mg/kg; 0.5 mg/kg; 10 mg/kg; 30 mg/kg; 50 mg/kg Administration: Gastric intubation; 30-120 days Result: reduced tumor growth and extended the mice's mean survival time (5 mg/kg); in contrast, the 50 mg/kg dose caused the MST in tumor-bearing mice to be shorter.

Absorption, Distribution and Excretion
Orally administered erythromycin is readily absorbed. Food intake does not appear to affect serum erythromycin concentrations. Individual differences exist in erythromycin absorption, which may affect absorption to varying degrees. The peak plasma concentration (Cmax) of erythromycin is 1.8 mcg/L, and the time to peak concentration (Tmax) is 1.2 hours. In a pharmacokinetic study, the serum AUC after oral administration of 500 mg erythromycin was 7.3 ± 3.9 mg·h/L. The bioavailability of erythromycin after oral administration varies greatly (18-45%) and is well-known to be easily degraded under acidic conditions. In patients with normal liver function, erythromycin is primarily concentrated in the liver and then excreted via bile. Less than 5% of the oral dose of erythromycin is excreted in the urine. The fate of most absorbed erythromycin is unexplained but is likely metabolized. Erythromycin is present in most body fluids and accumulates in leukocytes and inflammatory fluid. Erythromycin concentrations in cerebrospinal fluid are low; however, in patients with meningitis, erythromycin diffusion across the blood-brain barrier is increased, possibly due to easier drug penetration into inflamed tissues. Erythromycin can cross the placental barrier. In healthy subjects, the clearance rate after intravenous injection of 125 mg erythromycin was 0.53 ± 0.13 L/h/kg. A clinical study involving healthy subjects and patients with cirrhosis found significantly reduced erythromycin clearance in patients with severe cirrhosis. The clearance rate in cirrhotic patients was 42.2 ± 10.1 L/h, compared to 113.2 ± 44.2 L/h in healthy subjects. Oral erythromycin is primarily absorbed in the duodenum. Bioavailability varies among individuals and is influenced by various factors, including the specific erythromycin derivative, dosage form, acid stability of the derivative, the presence of food in the gastrointestinal tract, and gastric emptying time. Oral absorption of erythromycin is slow. Peak serum concentrations range from 0.1 to 4.8 μg/mL, depending on the dosage form and coating used. Erythromycin has an oral absorption rate of less than 50%, and it is easily degraded by gastric acid. It is absorbed in the small intestine (primarily the duodenum in humans) in the form of erythromycin base. Erythromycin readily diffuses into intracellular fluid and exhibits antibacterial activity in almost all sites except the brain and cerebrospinal fluid. Erythromycin can penetrate prostatic fluid, reaching a concentration approximately 40% of its plasma concentration. The concentration in middle ear effusion is only 50% of its serum concentration, and therefore may be insufficient to treat otitis media caused by Haemophilus influenzae. The protein binding rate of erythromycin base is approximately 70% to 80%, while esterified erythromycin has an even higher protein binding rate, reaching up to 96%. Erythromycin can cross the placenta; the drug concentration in fetal plasma is approximately 5% to 20% of the concentration in maternal circulation. The drug concentration in breast milk is approximately 50% of the concentration in serum. In an in vitro human skin model, 10-20 mg of erythromycin dissolved in a solvent containing dimethylacetamide and 95% ethanol, when applied topically, is absorbed by the stratum corneum. A 2% erythromycin solution (dissolved in a solvent containing 77% ethanol, polyethylene glycol, and acetone) applied to the skin twice daily did not appear to be absorbed systemically. It is unclear whether erythromycin is absorbed from intact or broken skin, wounds, or mucous membranes after topical application of an erythromycin-containing ointment. For more complete data on absorption, distribution, and excretion of erythromycin (13 in total), please visit the HSDB record page. Four hours after oral administration of 250 mg erythromycin base, peak plasma concentrations were 0.3–0.5 μg/mL; after oral administration of 500 mg erythromycin tablets, peak plasma concentrations were 0.3–1.9 μg/mL. Several erythromycin esters have been prepared to improve stability and promote absorption. Oral administration of stearates does not significantly change plasma concentrations of erythromycin. …It readily diffuses into intracellular fluid, and its antibacterial activity…is achieved in all sites except the brain and cerebrospinal fluid. …One of the few antibiotics that can penetrate prostatic fluid, at concentrations approximately 40% of those in plasma. …The degree of binding to plasma proteins varies…it may exceed 70% in all drug forms. /Erythromycin/
Erythromycin base is readily absorbed from the upper small intestine; erythromycin can be inactivated by gastric juices…food in the stomach delays its final absorption. /Erythromycin/
Erythromycin can cross the placental barrier; the drug concentration in fetal plasma is approximately 5-20% of the concentration in maternal circulation. /Erythromycin/
For more complete data on the absorption, distribution, and excretion of erythromycin stearate (11 types), please visit the HSDB record page.

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Metabolism/Metabolites
After oral administration, the first-pass metabolism in the liver makes a significant contribution to the metabolism of erythromycin. Erythromycin is partially metabolized by the CYP3A4 enzyme to N-demethylerythromycin. Erythromycin can also be hydrolyzed to its dehydrated form (dehydrated erythromycin [AHE] and other metabolites), and acidic conditions can promote this process. AHE is inactive against microorganisms but can inhibit hepatic drug oxidation, and is therefore considered an important factor in erythromycin drug interactions.
Twenty hours after oral administration of 10 mg erythromycin to rats, approximately 37-43% of the administered radioactive material was recovered in the intestines and feces, 27.2-36.1% in the urine, and 21-29% in exhaled air. Erythromycin is rapidly metabolized in the liver, primarily through demethylation, and excreted in bile as des-N-methylerythromycin, the major metabolite found only in rat bile and intestinal contents. The isotopic methyl group is excreted as carbon dioxide in exhaled air.
It is hydrolyzed in the small intestine and tissues to form erythromycin.
Primarily metabolized in the liver—less than 5% of the administered dose of the active form is recovered in the urine after oral administration. Erythromycin is partially metabolized by CYP3A4, leading to various drug interactions.
Half-life: 0.8-3 hours

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Biological half-life
One study showed that the elimination half-life of oral erythromycin is 3.5 hours, while another study showed a range of 2.4-3.1 hours. Repeated administration of erythromycin leads to a prolonged elimination half-life.
...The serum elimination half-life of erythromycin is approximately 1.6 hours.
The serum half-life in normal subjects is 2 hours, and in anuric subjects it is 4-6 hours.

Toxicity Summary
Erythromycin's mechanism of action involves penetrating the bacterial cell membrane and reversibly binding to the 50S subunit of the bacterial ribosome or near the P site (donor site), thereby blocking the binding of tRNA (transfer RNA) to the donor site. The transport of the peptide chain from the A site (receptor site) to the P site (donor site) is prevented, thus inhibiting subsequent protein synthesis. Erythromycin is effective only against bacteria in the active division phase. The exact mechanism by which erythromycin reduces acne vulgaris lesions is not fully understood; however, its efficacy appears to be partly attributable to the drug's antibacterial activity. Interactions
Erythromycin is metabolized by CYP3A, and co-administration with CYP3A isoenzyme inhibitors may lead to increased plasma concentrations of erythromycin. Some evidence suggests that concomitant use of oral erythromycin with CYP3A inhibitors (such as fluconazole, ketoconazole, itraconazole, diltiazem, and verapamil) increases the incidence of sudden cardiac death, possibly due to elevated plasma erythromycin concentrations leading to QT interval prolongation (a dose-related effect of erythromycin) and an increased risk of serious ventricular arrhythmias. Therefore, some studies recommend avoiding the concurrent use of erythromycin and potent CYP3A inhibitors. Erythromycin may interact with astemizole and terfenadine (both discontinued in the US), potentially causing serious cardiovascular adverse reactions. Some evidence suggests that erythromycin may alter the metabolism of astemizole and terfenadine by inhibiting the cytochrome P-450 microsomal enzyme system. Although erythromycin has been shown to significantly reduce the clearance of the active carboxylic acid metabolite of terfenadine, the effect of this macrolide on the concentration of unmetabolized terfenadine is not fully elucidated and appears to exhibit individual variability. In studies of individuals with enhanced metabolism of dextromethorphan or debromoquinolones, erythromycin significantly inhibited the clearance of the active metabolite of terfenadine in all such individuals, but had a measurable effect on unmetabolized terfenadine in only one-third of the individuals. Furthermore, erythromycin is known to inhibit the enzyme system responsible for the metabolism of astemizole. Some patients receiving astemizole or terfenadine have reported QT interval prolongation and ventricular tachycardia (including torsades de pointes) when concurrently taking erythromycin or the structure-related cyclic lactone antibiotic traromycin (currently discontinued in the US). In rare cases, cardiac arrest and death have been reported in patients receiving combined erythromycin and terfenadine. Therefore, when terfenadine and astemizole were marketed in the US, these antihistamines were contraindicated in patients receiving erythromycin, clarithromycin, or traromycin. Furthermore, concomitant use of astemizole or terfenadine with azithromycin is not recommended, although limited data suggest that azithromycin does not alter the metabolism of terfenadine. Although in vitro studies have shown that erythromycin, when used in combination with penicillins, streptomycins, sulfonamides, rifampin, or chloramphenicol, exhibits varying degrees of additive or synergistic effects against certain microorganisms, the clinical significance of these reports remains undetermined. In vitro studies have observed antagonistic bactericidal activity between erythromycin and clindamycin. Furthermore, antagonistic effects have been reported when bacteriostatic and bactericidal drugs are used together, but there is no conclusive clinical evidence to confirm such antagonism. Concomitant use of erythromycin in patients receiving high-dose theophylline therapy leads to decreased theophylline clearance, increased serum theophylline concentrations, and prolonged serum half-life of bronchodilators. Patients taking more than 1.5 grams of erythromycin daily for more than 5 days are most likely to experience drug interactions. Patients receiving theophylline therapy should be closely monitored for signs of theophylline toxicity when concurrently taking erythromycin; serum theophylline concentrations should be monitored, and the dose of bronchodilators should be reduced if necessary. Although further research is needed and its clinical significance remains undetermined, there is evidence that the co-administration of erythromycin with theophylline can also lead to a decrease in serum erythromycin concentrations, and may even result in subtherapeutic concentrations. For more complete data on erythromycin interactions (22 in total), please visit the HSDB record page. A 77-year-old woman receiving 7.5 mg warfarin daily for maintenance therapy and 500 mg of oral erythromycin stearate four times daily reported a prothrombin time of 64 seconds (compared to 11 seconds in the control group). Non-human toxicity values: Rat oral LD50: 9272 mg/kg; Mouse intraperitoneal LD50: 463 mg/kg; Mouse subcutaneous LD50: 1800 mg/kg; Mouse intramuscular LD50: 426 mg/kg. For more complete data on non-human toxicity values of erythromycin (6 in total), please visit the HSDB record page.

[1]. Erythromycin. Med Clin North Am. 1982 Jan;66(1):79-89.

[2]. Activity of azithromycin or erythromycin in combination with antimalarial drugs against multidrug-resistant Plasmodium falciparum in vitro. Acta Trop. 2006 Dec;100(3):185-91. Epub 2006 Nov 28.

[3]. Antitumor effect of erythromycin in mice. Chemotherapy. 1995 Jan-Feb. 41(1):59-69.

[4]. Neuroprotective effects of erythromycin on cerebral ischemia reperfusion-injury and cell viability after oxygen-glucose deprivation in cultured neuronal cells. Brain Res. 2014 Nov 7. 1588:159-67.

Therapeutic Uses
Macrolide antibiotics; gastrointestinal drugs; protein synthesis inhibitors. Veterinary medicine: In veterinary medicine, erythromycin is used to treat clinical and subclinical mastitis in lactating cows, infectious diseases caused by erythromycin-sensitive bacteria (cattle, sheep, pigs, poultry), and chronic respiratory diseases in poultry caused by mycoplasma. Erythromycin can be used as an alternative treatment for anthrax. For spontaneous or endemic anthrax caused by susceptible strains of Bacillus anthracis, including clinically manifested gastrointestinal anthrax, inhalation anthrax, meningeal anthrax, and anthrax septicemia, injectable penicillin is generally considered the first-line treatment, but intravenous ciprofloxacin or doxycycline is also often recommended. For patients allergic to penicillin, erythromycin is recommended as an alternative to penicillin G for spontaneous or endemic anthrax. /Not included on US product label/ Erythromycin can be used topically to treat acne vulgaris. Treatment of acne vulgaris must be individualized and frequently adjusted based on the primary acne lesion type and treatment response. Topical anti-infectives, including erythromycin, are generally effective in treating mild to moderate inflammatory acne. However, the use of topical anti-infectives alone can lead to bacterial resistance; this resistance is associated with reduced clinical efficacy. Topical erythromycin is particularly effective when used in combination with benzoyl peroxide or topical retinoids. Clinical studies have shown that combination therapy can reduce the total number of lesions by 50% to 70%. /Included in US product label/
For more complete data on the therapeutic uses of erythromycin (of 23 types), please visit the HSDB record page.
Its action and uses are the same as erythromycin.
Erythromycin may be effective in disseminated gonococcal disease in pregnant women allergic to penicillin…13 patients…received 500 mg of erythromycin stearate…orally every 6 hours for 5 days, showing rapid clinical and bacteriological responses.
Antibacterial Agents
Veterinary Drugs: Antibacterial Agents

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Drug Warnings
Some commercially available products containing erythromycin lactobionate powder for injection contain benzyl alcohol as a preservative. Although a causal relationship has not been established, the use of benzyl alcohol-containing injections has been associated with neonatal poisoning. These neonatal poisonings appear to be due to the injection of large doses (approximately 100-400 mg/kg daily) of benzyl alcohol. While the use of benzyl alcohol-containing medications in neonates should be avoided whenever possible, the American Academy of Pediatrics states that the presence of small amounts of benzyl alcohol in commercially available injections should not be a reason to prohibit their use in neonates. Erythromycin Lactobionate: Adverse cardiac reactions requiring cardiopulmonary resuscitation (e.g., bradycardia, hypotension, cardiac arrest, arrhythmias) have been reported in some neonates infected with Ureaplasma urealyticum who received intravenous treatment with erythromycin lactobionate. Some clinicians have noted that these adverse reactions may be related to the serum concentration of the drug and/or the infusion rate. Studies have shown that prolonging the intravenous infusion time of erythromycin lactobionate (e.g., exceeding 60 minutes) may reduce such adverse cardiac reactions. However, other studies have indicated that some individuals may have a higher risk of erythromycin-induced adverse cardiac reactions, and reducing the intravenous infusion rate may reduce but not eliminate this risk. Further studies are needed to determine the pharmacokinetics and safety of erythromycin lactobionate in neonates. Erythromycin lactobionate /
Maternal use generally compatible with breastfeeding: Erythromycin: Signs or symptoms reported in infants or effects on lactation: None. /Excerpt from Table 6/
Potential adverse reactions in the fetus: Unknown. Potential side effects in breastfed infants: Unknown, although theoretically may cause infant diarrhea. Note: At high doses, it can cross the placenta, with fetal blood concentrations being 24% of maternal blood concentrations; drug concentrations in breast milk may be higher than maternal serum concentrations. FDA Classification: B (B = Laboratory animal studies have not shown fetal risk, but there are no controlled studies in pregnant women; or animal studies have shown adverse effects (excluding decreased fertility), but controlled studies in pregnant women have not shown fetal risk in early pregnancy and there is no evidence of fetal risk in late pregnancy.) /Excerpt from Table II/
For more complete data on drug warnings for erythromycin (17 in total), please visit the HSDB record page.
…Erythromycin and its derivatives rarely cause serious adverse reactions. Pharmacodynamics Macrolide antibiotics, such as erythromycin, treat bacterial infections by inhibiting bacterial growth through protein synthesis and translation. Erythromycin does not affect nucleic acid synthesis. This drug has been shown to be effective against most microbial strains and is effective in treating infections in vitro and clinically. Nevertheless, bacterial susceptibility testing is still very important before using this antibiotic, as drug resistance is a common problem that can affect treatment outcomes. Notes on Antimicrobial Resistance, Pseudomembranous Colitis, and Hepatotoxicity Many Haemophilus influenzae strains are resistant to erythromycin monotherapy but are sensitive to erythromycin in combination with sulfonamides. It is noteworthy that erythromycin-resistant Staphylococcus aureus may develop during treatment with erythromycin and/or sulfonamides. Most antimicrobial drugs, including erythromycin, have been reported to cause pseudomembranous colitis, ranging in severity from mild to life-threatening. Therefore, physicians should consider a diagnosis of pseudomembranous colitis in patients who develop diarrhea after taking antimicrobial drugs. Erythromycin can cause liver dysfunction, cholestatic jaundice, and abnormal liver transaminases, especially when erythromycin esters are used.

C37H67NO13

733.9268

733.461

C, 60.55; H, 9.20; N, 1.91; O, 28.34

114-07-8

Erythromycin-d6;959119-25-6;Erythromycin-d3;959119-26-7;Erythromycin Ethylsuccinate;1264-62-6;Erythromycin stearate;643-22-1;Erythromycin lactobionate;3847-29-8;Erythromycin (aspartate);30010-41-4;Erythromycin thiocyanate;7704-67-8;Erythromycin A dihydrate;59319-72-1;Erythromycin-13C,d3;2378755-50-9

12560

White to off-white solid powder

1.2±0.1 g/cm3

818.4±65.0 °C at 760 mmHg

138-140ºC

448.8±34.3 °C

0.0±0.6 mmHg at 25°C

1.535

Streptomyces erythreHs

2.83

5

14

7

51

1180

18

O([C@@]1([H])[C@@]([H])([C@]([H])(C([H])([H])[C@@]([H])(C([H])([H])[H])O1)N(C([H])([H])[H])C([H])([H])[H])O[H])[C@@]1([H])[C@@](C([H])([H])[H])(C([H])([H])[C@@]([H])(C([H])([H])[H])C([C@]([H])(C([H])([H])[H])[C@]([H])([C@@](C([H])([H])[H])([C@@]([H])(C([H])([H])C([H])([H])[H])OC([C@]([H])(C([H])([H])[H])[C@]([H])([C@]1([H])C([H])([H])[H])O[C@@]1([H])C([H])([H])[C@](C([H])([H])[H])([C@]([H])([C@]([H])(C([H])([H])[H])O1)O[H])OC([H])([H])[H])=O)O[H])O[H])=O)O[H]

ULGZDMOVFRHVEP-RWJQBGPGSA-N

InChI=1S/C37H67NO13/c1-14-25-37(10,45)30(41)20(4)27(39)18(2)16-35(8,44)32(51-34-28(40)24(38(11)12)15-19(3)47-34)21(5)29(22(6)33(43)49-25)50-26-17-36(9,46-13)31(42)23(7)48-26/h18-26,28-32,34,40-42,44-45H,14-17H2,1-13H3/t18-,19-,20+,21+,22-,23+,24+,25-,26+,28-,29+,30-,31+,32-,34+,35-,36-,37-/m1/s1

(3R,4S,5S,6R,7R,9R,11R,12R,13S,14R)-6-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-14-ethyl-7,12,13-trihydroxy-4-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,7,9,11,13-hexamethyloxacyclotetradecane-2,10-dione

Emycin; HSDB 3074; HSDB-3074; HSDB3074; Eryc-125; Eryc-250; Erythromycin

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 (136.25 mM)
Ethanol : ~100 mg/mL
H2O : 1 mg/mL (1.36 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (2.83 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 20.8 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: ≥ 2.08 mg/mL (2.83 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 20.8 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: ≥ 2.08 mg/mL (2.83 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 20.8 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: ≥ 2.08 mg/mL (2.83 mM)

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Solubility in Formulation 5: 5 mg/mL (6.81 mM) in 0.5% CMC-Na 0.1% Tween-80 (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.

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