In primary bronchial epithelial cells from asthmatics, azithromycin (2 μM) increases rhinovirus-induced IFNβ expression. This is linked to over-expression of RIG-I like receptors and suppression of viral multiplication. In asthmatic primary bronchial epithelial cells, azithromycin (2 μM)-enhanced viral-induced IFNβ production is diminished by MDA5 knockdown, but not by RIG-I knockdown[1]. Without altering NF-κB, azithromycin selectively lowers MMP-9 mRNA and protein levels in endotoxin-challenged monocytic THP-1 cells[2].

Azithromycin (50 mg/kg) has no effect on bronchoalveolar lavage inflammatory markers and LDH levels in a mouse model of asthma exacerbation. Azithromycin produces neither general inflammatory parameters nor LDH release in a mouse model of asthma exacerbation, and augments expression of interferon-stimulated genes and the pattern recognition receptor MDA5 but not RIG-I in aggravating mice[1].

Absorption, Distribution and Excretion
Bioavailability of azithromycin is 37% following oral administration. Absorption is not affected by food. Macrolide absorption in the intestines is believed to be mediated by P-glycoprotein (ABCB1) efflux transporters, which are known to be encoded by the _ABCB1_ gene.
Biliary excretion of azithromycin, primarily as unchanged drug, is a major route of elimination. Over a 1 week period, approximately 6% of the administered dose is found as unchanged drug in urine.
After oral administration, azithromycin is widely distributed in tissues with an apparent steady-state volume of distribution of 31.1 L/kg. Significantly greater azithromycin concentrations have been measured in the tissues rather than in plasma or serum,. The lung, tonsils and prostate are organs have shown a particularly high rate of azithromycin uptake. This drug is concentrated within macrophages and polymorphonucleocytes, allowing for effective activity against Chlamydia trachomatis. In addition, azithromycin is found to be concentrated in phagocytes and fibroblasts, shown by in vitro incubation techniques. In vivo studies demonstrate that concentration in phagocytes may contribute to azithromycin distribution to inflamed tissues.
Mean apparent plasma cl=630 mL/min (following single 500 mg oral and i.v. dose)
Biliary excretion of azithromycin, predominantly as unchanged drug is a major route of elimination following oral administration.
Azithromycin is rapidly absorbed from the GI tract after oral administration; absorption of the drug is incomplete but exceeds that of erythromycin. The absolute oral bioavailability of azithromycin is reported to be approximately 34-52% with single doses of 500 mg to 1.2 g administered as various oral dosage forms. Limited evidence indicates that the low bioavailability of zithromycin results from incomplete GI absorption rather acid degradation of the drug or extensive first-pss metabolism.
Azithromycin appears to be distributed into most body tissues and fluids after oral or IV administration. The extensive tissue uptake of azithromycin has been attributed to cellular uptake of this basic antibiotic into relatively acidic lysosomes as a result of iron trapping and to an energy-dependent pathway associated with the nucleoside transport system.
Because of rapid distribution into tissues and high intracellular concentrations of azithromycin, tissue concentrations of the drug generally exceed plasma concentrations by 10- to 100-fold following single dose administration; with multiple dosing, the tissue-to-plasma ratio increases.
For more Absorption, Distribution and Excretion (Complete) data for AZITHROMYCIN (10 total), please visit the HSDB record page.

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Metabolism / Metabolites
In vitro and in vivo studies to assess the metabolism of azithromycin have not been performed, however, this drug is eliminated by the liver,.
The principal route of biotransformation involves N-demethylation of the desosamine sugar or at the 9a position on the macrolide ring. Other metabolic pathways include O-demethylation and hydrolysis and/or hydroxylation of the cladinose and desosamine sugar moieties and the macrolide ring. Up to 10 metabolites of azithromycin have been identified, and all are microbiologically inactive. While short-term administration of azithromycin produces hepatic accumulation of the drug and increases azithromycin demethylase activity, current evidence indicates that hepatic cytochrome p450 induction of inactivation via cytochrome-metabolite complex formation does not occur. In contrast to erythromycin, azithromycin does not inhibit its own metabolism via this pathway.

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Biological Half-Life
Terminal elimination half-life: 68 hours
An elimination half-life of 54.5 hours has been reported in children 4 months to 15 years of age receiving single or multiple oral doses of azithromycin.
Plasma azithromycin concentrations following a single 500-mg oral or IV dose decline in a polyphasic manner with a terminal elimination half-life averaging 68 hours. The high values for apparent steady-state volume of distribution (31.3-33.3 L/kg) and plasma clearance (630 mL/minute, 10.18 mL/minute per kg) of azithromycin suggest that the prolonged half-life is related to extensive uptake and subsequent release of the drug from tissues. The average tissue half-life of azithromycin is estimated to be 1-4 days. The half-life of the drug in peripheral leukocytes ranges from 34-57 hours.

Interactions
Because concomitant use of pimozide and other macrolides (e.g., clarithromycin) has increased pimozide concentrations and is associated with a risk of prolonged QT interval and serious cardiovascular effects, the manufacturer of pimozide states that concomitant use of pimozide and macrolides (including azithromycin) is contraindicated.
Although specific drug interaction studies have not been performed with azithromycin, concomitant use with other macrolides has resulted in increased phenytoin concentrations. Therefore, the patient should be carefully monitored if azithromycin and phenytoin are used concomitantly.
Although the single-dose extended-release oral suspension of azithromycin may be taken without regard to antacids containing magnesium hydroxide and/or aluminum hydroxide, conventional oral azithromycin preparations (tablets or oral suspension) should not be administered simultaneously with aluminum- or magnesium-containing antacids. A study using azithromycin capsules (no longer commercially available) indicate that administration of oral azithromycin 500 mg with an aluminum- and magnesium hydroxide-containing antacid resulted in a decreased rate of absorption of azithromycin as evidenced by 24% reduction in peak serum azithromycin concentrations; however, the extent of azithromycin absorption (AUC) was unaffected.
Although specific drug interaction studies have not been performed with azithromycin, concomitant use with other macrolides has resulted in increased concentrations of ergot alkaloids (ergotamine, dihydroergotamine). Therefore, the patient should be carefully monitored if azithromycin and ergot alkaloids are used concomitantly.
For more Interactions (Complete) data for AZITHROMYCIN (14 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Mice oral 3000-4000 mg/kg

[1]. Azithromycin augments rhinovirus-induced IFNβ via cytosolic MDA5 in experimental models of asthma exacerbation. Oncotarget. 2017 Mar 18.

[2]. Differential inhibition of activity, activation and gene expression of MMP-9 in THP-1 cells by azithromycin and minocycline versus bortezomib: A comparative study. PLoS One. 2017 Apr 3;12(4):e0174853.

Therapeutic Uses
Anti-Bacterial Agents
Azithromycin is used orally in children for the treatment of acute otitis media (AOM) caused by Haemophilus influenzae, M. catarrhalis, or S. pneumoniae. /Included in US product labeling/
Azithromycin is used orally for the treatment of pharyngitis and tonsillitis caused by Streptococcus pyogenes (group A beta-hemolytic streptococci) in adults and children when first-line therapy (penicillins) cannot be used. /Included in US product labeling/
Although further study is needed, azithromycin has been used in conjunction with an antimalarial agent (e.g., chloroquine, quinine, artesunate [not commercially available in the US]) for the treatment of uncomplicated malaria caused by Plasmodium falciparum, including multidrug-resistant strains. Azithromycin should not be used alone as monotherapy for the treatment of malaria. /NOT included in US product labeling/
For more Therapeutic Uses (Complete) data for AZITHROMYCIN (52 total), please visit the HSDB record page.

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Drug Warnings
Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen in treatment with macrolides, including azithromycin. Cases of torsades de pointes have been spontaneously reported during postmarketing surveillance in patients receiving azithromycin. Providers should consider the risk of QT prolongation which can be fatal when weighing the risks and benefits of azithromycin for at-risk groups including: patients with known prolongation of the QT interval, a history of torsades de pointes, congenital long QT syndrome, bradyarrhythmias or uncompensated heart failure; patients on drugs known to prolong the QT interval; or patients with ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia, and in patients receiving Class IA (quinidine, procainamide) or Class III (dofetilide, aminodarone, sotalol) antiarrhythmic agents. Elderly patients may be more susceptible to drug-associated effects on the QT interval.
Pregnancy risk category: B /NO EVIDENCE OF RISK IN HUMANS. Adequate, well controlled studies in pregnant women have not shown increased risk of fetal abnormalities despite adverse findings in animals, or, in the absents of adequate human studies, animal studies show no fetal risk. The chance of fetal harm is remote but remains a possibility./
The most frequent adverse effects of azithromycin involve the GI tract (i.e., diarrhea/loose stools, nausea, abdominal pain). While these adverse effects generally are mild to moderate in severity and occur less frequently than with oral erythromycin, adverse GI effects are the most frequent reason for discontinuing azithromycin therapy. Administration of conventional azithromycin tablets or oral suspension with food may improve GI tolerability.
Azithromycin has been detected in human milk. The drug should be used with caution in nursing women.
For more Drug Warnings (Complete) data for AZITHROMYCIN (30 total), please visit the HSDB record page.

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Pharmacodynamics
Macrolides stop bacterial growth by inhibiting protein synthesis and translation, treating bacterial infections. Azithromycin has additional immunomodulatory effects and has been used in chronic respiratory inflammatory diseases for this purpose.

C38H72N2O12

748.98

748.508

83905-01-5

Azithromycin hydrate;117772-70-0;Azithromycin-d3;163921-65-1;Azithromycin-13C,d3

447043

White to off-white solid powder

1.2±0.1 g/cm3

822.1±65.0 °C at 760 mmHg

113-115°C

451.0±34.3 °C

0.0±0.6 mmHg at 25°C

1.537

3.33

5

14

7

52

1150

18

CC[C@@H]1[C@@]([C@@H]([C@H](N(C[C@@H](C[C@@]([C@@H]([C@H]([C@@H]([C@H](C(=O)O1)C)O[C@H]2C[C@@]([C@H]([C@@H](O2)C)O)(C)OC)C)O[C@H]3[C@@H]([C@H](C[C@H](O3)C)N(C)C)O)(C)O)C)C)C)O)(C)O

MQTOSJVFKKJCRP-BICOPXKESA-N

InChI=1S/C38H72N2O12/c1-15-27-38(10,46)31(42)24(6)40(13)19-20(2)17-36(8,45)33(52-35-29(41)26(39(11)12)16-21(3)48-35)22(4)30(23(5)34(44)50-27)51-28-18-37(9,47-14)32(43)25(7)49-28/h20-33,35,41-43,45-46H,15-19H2,1-14H3/t20-,21-,22+,23-,24-,25+,26+,27-,28+,29-,30+,31-,32+,33-,35+,36-,37-,38-/m1/s1

(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one

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)

Solubility in Formulation 1: ≥ 2.5 mg/mL (3.34 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 (3.34 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 (3.34 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.)