Macrolide antibiotic; protein synthesis by targeting the bacterial ribosome; CYP3A4

Clarithromycin has a similar concentration-dependent block, with an IC50 of 45.7 μM [3]. Clarithromycin causes the formation of numerous intracytoplasmic vacuoles in all cell lines after 24 hours, particularly in HCT116 cells. Prolonged Clarithromycin (40, 80, and 160 μM) treatment alters cell proliferation and triggers apoptotic cell death in colorectal cancer (CRC). Clarithromycin re-administered to the cells increases the inhibition of cell proliferation. Re-adding 160 μM Clarithromycin after 48 hours of incubation causes cell proliferation to stop at 72 hours. Similar effects were observed in LS174T cells[4]. Clarithromycin (80 and 160 μM; 48 hours) significantly increases the LC3-II/LC3-I ratio in a dose- and time-dependent manner, peaking at 24 hours of treatment. This effect is associated with a decrease in p62/SQSTM1[4].

At 200 mg/kg, clarithromycin is active against four in vivo tests[5].The activity of clarithromycin alone and in combination with other antimycobacterial agents was evaluated in the beige (C57BL/6J bgj/bgj) mouse model of disseminated Mycobacterium avium complex (MAC) infection. A dose-response experiment was performed with clarithromycin at 50, 100, 200, or 300 mg/kg of body weight administered daily by gavage to mice infected with approximately 10(7) viable MAC. A dose-related reduction in spleen and liver cell counts was noted with treatment at 50, 100, and 200 mg/kg. The difference in cell counts between treatment at 200 and 300 mg/kg was not significant. Clarithromycin at 200 mg/kg of body weight was found to have activity against three additional MAC isolates (MICs for the isolates ranged from 1 to 4 micrograms/ml by broth dilution). Clarithromycin at 200 mg/kg in combination with amikacin, ethambutol, temafloxacin, or rifampin did not result in increased activity beyond that seen with clarithromycin alone. Clarithromycin in combination with clofazimine or rifabutin resulted in an increase in activity beyond that seen with clarithromycin alone. The combination of clarithromycin with clofazimine or rifabutin should be considered for evaluation in the treatment of human MAC infections.

Clarithromycin (Cla)-binding assay[4]
Cla binding to hERG1 was assessed by using fluorescently labeled 11-O-{3-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]propyl}-6-O-methyl-erythromycin A (shortly: 11-NBD-Cla), synthesized as reported52, on normal human embryonic kidney (HEK)293 cells transfected with hERG1 and different hERG1 mutants. Cells were seeded in 96-wells black assay plates at 1 × 104 cells/well in complete medium. After 24 h, cells were treated for 30 min with 10 µM 11-NBD-Cla at 37 °C. After a brief wash at room temperature with phosphate-buffered saline (PBS), fluorescence intensity was immediately measured with a Synergy H1 microplate reader (excitation/emission 463/536 nm). Cells were then lysed in 0.5% Triton X-100 for 15 min on ice and protein concentration was determined by Bio-Rad protein assay. Fluorescence intensity was normalized on total protein content, after subtracting the values obtained from HEK293 MOCK cells. The obtained data were normalized on the relative hERG1 expression in HEK293 cells transfected with the different mutants, shown in ref. 48. Obtained results are hence referred to as “11-NBD-Cla fluorescence increase relative to MOCK cells” in Fig. 3e.

Cell Proliferation Assay[4]
Cell Types: HCT116 cells
Tested Concentrations: 40, 80, and 160 µM
Incubation Duration: 24, 48, 72 hrs (hours)
Experimental Results: decreased HCT116 cell proliferation, although did not completely abolished it.

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Western Blot Analysis[4]
Cell Types: HCT116 cells
Tested Concentrations: 80 and 160 µM
Incubation Duration: 4, 24, 48 hrs (hours)
Experimental Results: A decrease of LC3-II and a re-increase of p62/SQSTM1 were observed at 48 hrs (hours) treatment.

Animal/Disease Models: Sixweeks old beige (C57BL/6J bgj/bgj) mice which had been infected with viable M. avium ATCC 49601[5]
Doses: 50, 100, 200, or 300 mg/kg
Route of Administration: Administered daily by gavage
Experimental Results: decreased organ cell counts compared with those in mice given no treatment at all doses. Had activity against three additional MAC isolates (MICs for the isolates ranged from 1 to 4 µg/mL by broth dilution) at 200 mg/kg.

Absorption, Distribution and Excretion
Clarithromycin is well-absorbed, acid stable and may be taken with food.
After a 250 mg tablet every 12 hours, approximately 20% of the dose is excreted in the urine as clarithromycin, while after a 500 mg tablet every 12 hours, the urinary excretion of clarithromycin is somewhat greater, approximately 30%.
Limited data are available on the distribution of clarithromycin in humans. Clarithromycin and 14-hydroxyclarithromycin appear to be distributed into most body tissues and fluids. Because of high intracellular concentrations of the drug, tissue concentrations are higher than serum concentrations. High concentrations of clarithromycin were present in tissue samples obtained from patients undergoing surgery. In patients who received 250-500 mg of clarithromycin orally every 12 hours for 3 days prior to surgery, peak clarithromycin concentrations in lung, tonsils, and nasal mucosa reportedly were attained 4 hours after administration and averaged 13.5-17.5, 5.3-6.5, and 5.9-8.3 mg/ kg, respectively; however, it has been suggested that these data may represent an overestimate of clarithromycin tissue concentrations because of the microbiologic assay's inability to distinguish between parent drug and its active metabolite. In children receiving clarithromycin suspension for otitis media at a dosage of 7.5 mg/kg every 12 hours for 5 doses, peak clarithromycin and 14- hydroxyclarithromycin concentrations in middle ear fluid were 2.5 and 1.3 ug/ mL, respectively; concomitant serum concentrations were 1.7 and 0.8 ug/mL, respectively. Results of studies in animals given radiolabeled clarithromycin or erythromycin indicate higher and more prolonged activity of clarithromycin in various body tissues, particularly the lung
Clarithromycin is absorbed rapidly from the GI tract after oral administration; GI absorption of the drug exceeds that of erythromycin.
Clarithromycin is eliminated by both renal and nonrenal mechanisms.
Following oral administration of a single 250-mg dose of radiolabeled clarithromycin in healthy men, approximately 38% of the dose (18% as clarithromycin) was excreted in urine, and 40% in feces (4% as clarithromycin), over 5 days. With oral administration of 250 or 500 mg of clarithromycin as tablets every 12 hours, approximately 20 or 30% of the respective dose is excreted unchanged in urine within 12 hours. After an oral clarithromycin dosage of 250 mg every 12 hours as the suspension, approximately 40% of the administered dose is excreted unchanged in urine. The principal metabolite found in urine is 14-hydroxyclarithromycin, which accounts for approximately 10-15% of the dose following administration of 250 or 500 mg of clarithromycin as tablets.
For more Absorption, Distribution and Excretion (Complete) data for Clarithromycin (6 total), please visit the HSDB record page.

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Metabolism / Metabolites
Hepatic - predominantly metabolized by CYP3A4 resulting in numerous drug interactions.
The principal metabolite found in urine is 14-hydroxyclarithromycin, which accounts for approximately 10-15% of the dose following administration of 250 or 500 mg of clarithromycin as tablets.
Clarithromycin is extensively metabolized in the liver, principally by oxidative N- demethylation and hydroxylation at the 14 position; hydrolytic cleavage of the cladinose sugar moiety also occurs in the stomach to a minor extent. Although at least 7 metabolites of clarithromycin have been identified, 14-hydroxyclarithromycin is the principal metabolite in serum and the only one with substantial antibacterial activity. While both the R- and S-epimers of 14-hydroxyclarithromycin are formed in vivo, the R-epimer is present in greater amounts and has the greatest antimicrobial activity. Metabolism of clarithromycin appears to be saturable since the amount of 14-hydroxyclarithromycin after an 800-mg dose of the parent drug is only marginally greater than that after a 250-mg dose.
Following oral administration of a single 250-mg dose of radiolabeled clarithromycin in healthy men, approximately 38% of the dose (18% as clarithromycin) was excreted in urine, and 40% in feces (4% as clarithromycin), over 5 days. ... The principal metabolite found in urine is 14-hydroxyclarithromycin, which accounts for approximately 10-15% of the dose following administration of 250 or 500 mg of clarithromycin as tablets.

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Biological Half-Life
3-4 hours
Following oral administration of single 250-mg or 1.2-g doses of clarithromycin conventional tablets in healthy men, the elimination half-life averaged 4 or 11 hours, respectively. During multiple dosing every 12 hours, the elimination half-life of clarithromycin reportedly increased from 3-4 hours following a 250-mg dose (conventional tablets) every 12 hours to 5-7 hours following a 500-mg dose every 8-12 hours; the half-life of 14-hydroxyclarithromycin increased from 5-6 hours with a 250-mg dose to 7-9 hours with a 500-mg dose. When clarithromycin is administered as the oral suspension, the elimination half-life of the drug and of its 14-hydroxy metabolite appear to be similar to those observed at steady-state following administration of equivalent doses of clarithromycin as tablets.

Hepatotoxicity
Clarithromycin, like other macrolide antibiotics, has been linked to a low rate of acute, transient and usually asymptomatic elevations in serum aminotransferase levels which occur in 1% to 2% of patients treated for short periods and a somewhat higher proportion of patients given clarithromycin long term. Asymptomatic elevations in serum enzymes are particularly common among elderly patients given higher doses of clarithromycin.
Clarithromycin can also cause acute, clinically apparent liver injury with jaundice, which is estimated to occur in 3.8 per 100,000 prescriptions. The liver injury usually appears within the first 1 to 3 weeks after initiation of treatment and can arise after clarithromycin is stopped. The pattern of liver enzyme elevations varies, but the resulting hepatitis is often cholestatic and can be prolonged (Case 1). Allergic signs and symptoms have not been consistently reported. While cholestatic hepatitis is most typical of clarithromycin induced liver injury, rare cases with hepatocellular injury and abrupt onset have been described. These hepatocellular cases are more likely to be severe and can result in acute liver failure. However, in most instances, recovery occurs within 4 to 8 weeks of withdrawal of the medication. The typical latency, clinical pattern and course of the cholestatic hepatitis due to clarithromycin resembles that of the other macrolide antibiotics.
Likelihood score: B (highly likely cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Because of the low levels of clarithromycin in breastmilk and safe administration directly to infants, it is acceptable in nursing mothers. The small amounts in milk are unlikely to cause adverse effects in the infant. Monitor the infant for possible effects on the gastrointestinal flora, such as diarrhea, candidiasis (thrush, diaper rash). Unconfirmed epidemiologic evidence indicates that the risk of infantile hypertrophic pyloric stenosis might be increased by maternal use of macrolide antibiotics during the first two weeks of breastfeeding, but others have questioned this relationship.
◉ Effects in Breastfed Infants
A cohort study of infants diagnosed with infantile hypertrophic pyloric stenosis found that affected infants were 2.3 to 3 times more likely to have a mother taking a macrolide antibiotic during the 90 days after delivery. Stratification of the infants found the odds ratio to be 10 for female infants and 2 for male infants. All of the mothers of affected infants nursed their infants. Most of the macrolide prescriptions were for erythromycin, but only 1.7% were for clarithromycin. However, the authors did not state which macrolide was taken by the mothers of the affected infants.
A study comparing the breastfed infants of mothers taking amoxicillin to those taking a macrolide antibiotic found no instances of pyloric stenosis. However, most of the infants exposed to a macrolide in breastmilk were exposed to roxithromycin. Only 6 of the 55 infants exposed to a macrolide were exposed to clarithromycin. Adverse reactions occurred in 12.7% of the infants exposed to macrolides which was similar to the rate in amoxicillin-exposed infants. Reactions included rash, diarrhea, loss of appetite, and somnolence.
A retrospective database study in Denmark of 15 years of data found a 3.5-fold increased risk of infantile hypertrophic pyloric stenosis in the infants of mothers who took a macrolide during the first 13 days postpartum, but not with later exposure. The proportion of infants who were breastfed was not known, but probably high. The proportion of women who took each macrolide was also not reported.
Two meta-analyses failed to demonstrate a relationship between maternal macrolide use during breastfeeding and infantile hypertrophic pyloric stenosis.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
~ 70% protein bound

[1]. Clarithromycin. A review of its antimicrobial activity, pharmacokinetic properties and therapeutic potential. Drugs. 1992 Jul;44(1):117-64.

[2]. An in vitro study on the metabolism and possible drug interactions of rokitamycin, a macrolide antibiotic, using human liver microsomes. Drug Metab Dispos. 1999 Jul;27(7):776-85.

[3]. Characterization of the inhibitory effects of erythromycin and clarithromycin on the HERG potassium channel. Mol Cell Biochem. 2003 Dec;254(1-2):1-7.

[4]. Clarithromycin inhibits autophagy in colorectal cancer by regulating the hERG1 potassium channel interaction with PI3K. Cell Death Dis. 2020 Mar 2;11(3):161.

[5]. Activity of clarithromycin against Mycobacterium avium complex infection in beige mice. Antimicrob Agents Chemother. 1992 Nov;36(11):2413-7.

Clarithromycin can cause developmental toxicity according to state or federal government labeling requirements.
Clarithromycin is the 6-O-methyl ether of erythromycin A, clarithromycin is a macrolide antibiotic used in the treatment of respiratory-tract, skin and soft-tissue infections. It is also used to eradicate Helicobacter pylori in the treatment of peptic ulcer disease. It prevents bacteria from growing by interfering with their protein synthesis. It has a role as an antibacterial drug, a protein synthesis inhibitor, an environmental contaminant and a xenobiotic.
Clarithromycin is an antibacterial prescription medicine approved by the U.S. Food and Drug Administration (FDA) to treat certain bacterial infections, such as community-acquired pneumonia, throat infections (pharyngitis), acute sinus infections, and others. Clarithromycin is also FDA-approved to both prevent and treat Mycobacterium Avium complex (MAC) infection, another type of bacterial infection.
Community-acquired pneumonia, a bacterial respiratory disease, and disseminated MAC infection can be opportunistic infections (OIs) of HIV. An OI is an infection that occurs more frequently or is more severe in people with weakened immune systems—such as people with HIV—than in people with healthy immune systems.
Clarithromycin, a semisynthetic macrolide antibiotic derived from erythromycin, inhibits bacterial protein synthesis by binding to the bacterial 50S ribosomal subunit. Binding inhibits peptidyl transferase activity and interferes with amino acid translocation during the translation and protein assembly process. Clarithromycin may be bacteriostatic or bactericidal depending on the organism and drug concentration.
Clarithromycin is a Macrolide Antimicrobial. The mechanism of action of clarithromycin is as a Cytochrome P450 3A4 Inhibitor, and Cytochrome P450 3A Inhibitor, and P-Glycoprotein Inhibitor.
Clarithromycin is a semisynthetic macrolide antibiotic used for a wide variety of mild-to-moderate bacterial infections. Clarithromycin has been linked to rare instances of acute liver injury that can be severe and even fatal.
Clarithromycin is a semisynthetic 14-membered ring macrolide antibiotic. Clarithromycin binds to the 50S ribosomal subunit and inhibits RNA-dependent protein synthesis in susceptible organisms. Clarithromycin has been shown to eradicate gastric MALT (mucosa-associated lymphoid tissue) lymphomas, presumably due to the eradication of tumorigenic Helicobacter pylori infection. This agent also acts as a biological response modulator, possibly inhibiting angiogenesis and tumor growth through alterations in growth factor expression. (NCI04)
A semisynthetic macrolide antibiotic derived from ERYTHROMYCIN that is active against a variety of microorganisms. It can inhibit protein synthesis in bacteria by reversibly binding to the 50S ribosomal subunits. This inhibits the translocation of aminoacyl transfer-RNA and prevents peptide chain elongation.
See also: Clarithromycin lactobionate (is active moiety of); Amoxicillin; clarithromycin; lansoprazole (component of); Amoxicillin; clarithromycin; vonoprazan fumarate (component of) ... View More ...

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Drug Indication
An alternative medication for the treatment of acute otitis media caused by H. influenzae, M. catarrhalis, or S. pneumoniae in patients with a history of type I penicillin hypersensitivity. Also for the treatment of pharyngitis and tonsillitis caused by susceptible Streptococcus pyogenes, as well as respiratory tract infections including acute maxillary sinusitis, acute bacterial exacerbations of chronic bronchitis, mild to moderate community-acquired pneuomia, Legionnaires' disease, and pertussis. Other indications include treatment of uncomplicated skin or skin structure infections, helicobacter pylori infection, duodenal ulcer disease, bartonella infections, early Lyme disease, and encephalitis caused by Toxoplasma gondii (in HIV infected patients in conjunction with pyrimethamine). Clarithromycin may also decrease the incidence of cryptosporidiosis, prevent the occurence of α-hemolytic (viridans group) streptococcal endocarditis, as well as serve as a primary prevention for Mycobacterium avium complex (MAC) bacteremia or disseminated infections (in adults, adolescents, and children with advanced HIV infection). Clarithromycin is indicated in combination with [vonoprazan] and [amoxicillin] as co-packaged triple therapy to treat _Helicobacter pylori_ (_H. pylori_) infection in adults.
FDA Label
Treatment of Helicobacter spp. infections
Treatment of Helicobacter spp. infections

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Mechanism of Action
Clarithromycin is first metabolized to 14-OH clarithromycin, which is active and works synergistically with its parent compound. Like other macrolides, it then penetrates bacteria cell wall and reversibly binds to domain V of the 23S ribosomal RNA of the 50S subunit of the bacterial ribosome, blocking translocation of aminoacyl transfer-RNA and polypeptide synthesis. Clarithromycin also inhibits the hepatic microsomal CYP3A4 isoenzyme and P-glycoprotein, an energy-dependent drug efflux pump.
Clarithromycin usually is bacteriostatic, although it may be bactericidal in high concentrations or against highly susceptible organisms. Bactericidal activity has been observed against Streptococcus pyogenes, S. pneumoniae, Haemophilus influenzae, and Chlamydia trachomatis. Clarithromycin inhibits protein synthesis in susceptible organisms by penetrating the cell wall and binding to 50S ribosomal subunits, thereby inhibiting translocation of aminoacyl transfer-RNA and inhibiting polypeptide synthesis. The site of action of clarithromycin appears to be the same as that of erythromycin, clindamycin, lincomycin, and chloramphenicol.

C38H69NO13

747.95

747.476

C, 61.02; H, 9.30; N, 1.87; O, 27.81

81103-11-9

Clarithromycin-13C,d3;Clarithromycin-d3;959119-22-3

84029

Colorless needles from chloroform + diisopropyl ether (1:2) ... Also reported as crystals from ethanol

1.2±0.1 g/cm3

805.5±65.0 °C at 760 mmHg

217-220ºC

440.9±34.3 °C

0.0±6.5 mmHg at 25°C

1.526

3.16

4

14

8

52

1190

18

O([C@@H]1O[C@H](C)C[C@H](N(C)C)[C@H]1O)[C@@H]1[C@@H](C)[C@H](O[C@@H]2O[C@@H](C)[C@H](O)[C@](C)(OC)C2)[C@@H](C)C(=O)O[C@H](CC)[C@](O)(C)[C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@]1(C)OC

AGOYDEPGAOXOCK-KCBOHYOISA-N

InChI=1S/C38H69NO13/c1-15-26-38(10,45)31(42)21(4)28(40)19(2)17-37(9,47-14)33(52-35-29(41)25(39(11)12)16-20(3)48-35)22(5)30(23(6)34(44)50-26)51-27-18-36(8,46-13)32(43)24(7)49-27/h19-27,29-33,35,41-43,45H,15-18H2,1-14H3/t19-,20-,21+,22+,23-,24+,25+,26-,27+,29-,30+,31-,32+,33-,35+,36-,37-,38-/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-12,13-dihydroxy-4-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-7-methoxy-3,5,7,9,11,13-hexamethyloxacyclotetradecane-2,10-dione

Abbott56268; A56268; A-56268; A 56268; A56268; Abbott 56268; A 56268; Clarithromycin; Abbott-56268; A-56268; brand name Biaxin.clarithromycin; 81103-11-9; Biaxin; 6-O-Methylerythromycin; Klaricid; Clarithromycine; Clathromycin; Macladin

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) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
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.)