Macrolide antibiotic; protein synthesis by targeting the bacterial ribosome; CYP3A4
The targets of Clarithromycin include:
1. Bacterial 50S ribosomal subunit: Inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit [1]
2. Human ether-a-go-go-related gene (HERG) potassium channel: Inhibits HERG channel current, with a half-maximal inhibitory concentration (IC50) of 18.6 μM [3]
3. HERG1 potassium channel and phosphatidylinositol 3-kinase (PI3K): Interacts with HERG1 to disrupt its binding to PI3K, thereby inhibiting the PI3K/Akt/mTOR signaling pathway [4]
.

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].

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1. Antimicrobial activity against bacteria: Clarithromycin exhibits potent in vitro activity against a broad range of microorganisms. For Gram-positive bacteria, the minimum inhibitory concentrations (MICs) against Streptococcus pneumoniae (penicillin-susceptible strains) are 0.03-0.12 μg/mL, and against Staphylococcus aureus (methicillin-susceptible strains) are 0.12-0.5 μg/mL. For Gram-negative bacteria, MICs against Haemophilus influenzae are 0.5-2 μg/mL, and against Moraxella catarrhalis are ≤0.03 μg/mL. For atypical pathogens, MICs against Mycoplasma pneumoniae are 0.015-0.06 μg/mL, against Chlamydia pneumoniae are 0.03-0.12 μg/mL, and against Legionella pneumophila are 0.03-0.25 μg/mL. It also shows activity against Mycobacterium avium complex (MAC), with MICs ranging from 0.25-8 μg/mL [1]
2. Effects on human liver microsomal CYP enzymes: When incubated with human liver microsomes, Clarithromycin (1-100 μM) inhibits cytochrome P450 3A4 (CYP3A4) activity (using midazolam as a substrate) with an IC50 of 8.2 μM. It has weak or no inhibitory effects on other CYP isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6) at concentrations up to 100 μM [2]
3. Inhibition of HERG potassium channel current: In HEK293 cells stably expressing the HERG potassium channel, Clarithromycin (1-100 μM) inhibits the HERG channel current in a concentration-dependent manner. At a concentration of 30 μM, it inhibits the peak HERG current by 72.3% ± 5.1%, and the IC50 value is 18.6 μM. The inhibition is reversible after washout of the drug [3]
4. Inhibition of autophagy in colorectal cancer cells: In human colorectal cancer cell lines (HCT116 and SW480), treatment with Clarithromycin (5-20 μM) for 24 hours reduces the conversion of LC3-I to LC3-II (detected by Western blot, with a 50%-70% decrease in the LC3-II/LC3-I ratio compared to the control group) and increases the accumulation of p62 (a marker of autophagic flux blockage). Immunofluorescence staining shows a significant decrease in the number of LC3 puncta (autophagosomes) in drug-treated cells. Additionally, Clarithromycin reduces the phosphorylation of Akt and mTOR (downstream targets of PI3K) in a dose-dependent manner [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.

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1. Efficacy against Mycobacterium avium complex (MAC) infection in beige mice: Beige mice (8-10 weeks old) were infected intravenously with 1×10⁷ colony-forming units (CFU) of MAC (strain 101). One day after infection, the mice were randomly divided into 3 groups (n=6 per group): vehicle control group (0.5% carboxymethylcellulose), low-dose Clarithromycin group (100 mg/kg), and high-dose Clarithromycin group (200 mg/kg). Drugs were administered by oral gavage once daily for 21 consecutive days. At the end of the treatment, the mice were euthanized, and the spleen and liver were harvested. The number of MAC CFU in tissue homogenates was determined by plating on Middlebrook 7H10 agar. The results showed that the high-dose Clarithromycin group had a 2.3-log reduction in spleen CFU and a 1.8-log reduction in liver CFU compared to the vehicle control group. The low-dose group had a 1.1-log reduction in spleen CFU and a 0.9-log reduction in liver CFU [5]
2. Tissue distribution in animals: In rats and dogs, after oral administration of Clarithromycin (20 mg/kg), the drug accumulates in various tissues (lung, tonsil, sinus mucosa, prostate) at concentrations 2-10 times higher than those in plasma. For example, in rat lung tissue, the maximum concentration (Cmax) of Clarithromycin is 12.5 μg/g, while the plasma Cmax is 1.8 μg/mL. The tissue half-life is also longer than the plasma half-life (6-8 hours vs. 3-4 hours) [1]
.

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.

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1. CYP enzyme inhibition assay using human liver microsomes: Human liver microsomes (pooled from multiple donors) were mixed with a NADPH-generating system (glucose-6-phosphate, glucose-6-phosphate dehydrogenase, NADP+) and a specific substrate for the target CYP isoform (e.g., midazolam for CYP3A4, phenacetin for CYP1A2, tolbutamide for CYP2C9). Different concentrations of Clarithromycin (0.1, 1, 10, 30, 100 μM) or vehicle control (DMSO, ≤0.1% final concentration) were added to the mixture. The reaction was initiated by adding the NADPH-generating system and incubated at 37°C for 30 minutes. The reaction was terminated by adding ice-cold acetonitrile containing an internal standard. After centrifugation (10,000 × g for 10 minutes), the supernatant was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to quantify the amount of the metabolite formed from the substrate. The inhibition rate of each CYP isoform was calculated as [1 - (metabolite concentration in drug group / metabolite concentration in control group)] × 100%, and the IC50 value was determined by fitting the concentration-inhibition curve [2]
2. HERG potassium channel current recording (patch-clamp assay): HEK293 cells stably expressing the human HERG gene were cultured in a medium containing 10% fetal bovine serum. Cells were dissociated into single cells and placed in a recording chamber filled with extracellular solution (containing NaCl, KCl, CaCl2, MgCl2, glucose, HEPES). A glass micropipette (resistance 2-5 MΩ) filled with intracellular solution (containing KCl, MgATP, EGTA, HEPES) was used to form a whole-cell patch-clamp configuration. After achieving a stable seal (>1 GΩ), the membrane potential was clamped at -80 mV. HERG currents were elicited by a voltage protocol: a 2-second depolarization step to +40 mV (to activate the HERG channel), followed by a repolarization step to -50 mV (to record the tail current). Different concentrations of Clarithromycin (1, 10, 30, 100 μM) were added to the extracellular solution, and the current was recorded 5 minutes after each concentration addition. The tail current amplitude was measured, and the concentration-response curve was fitted to calculate the IC50 [3]
.

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.

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1. Colorectal cancer cell autophagy assay (Western blot and immunofluorescence): Human colorectal cancer cells (HCT116 and SW480) were seeded into 6-well plates (for Western blot) or 24-well plates with coverslips (for immunofluorescence) at a density of 5×10⁵ cells/well (6-well) or 1×10⁴ cells/well (24-well). After 24 hours of culture, the medium was replaced with fresh medium containing different concentrations of Clarithromycin (5, 10, 20 μM) or vehicle control (DMSO, ≤0.1% final concentration). The cells were further cultured for 24 hours. For Western blot: Cells were lysed with RIPA buffer containing a protease inhibitor cocktail. The total protein concentration was determined using a BCA protein assay kit. Equal amounts of protein (30 μg) were separated by 12% SDS-PAGE and transferred to PVDF membranes. The membranes were blocked with 5% non-fat milk for 1 hour at room temperature, then incubated with primary antibodies against LC3, p62, phospho-Akt (p-Akt), phospho-mTOR (p-mTOR), and β-actin (internal control) overnight at 4°C. After washing with TBST, the membranes were incubated with horseradish peroxidase-conjugated secondary antibodies for 1 hour at room temperature. Protein bands were visualized using an enhanced chemiluminescence (ECL) reagent, and band intensities were quantified using ImageJ software. For immunofluorescence: Cells were fixed with 4% paraformaldehyde for 15 minutes, permeabilized with 0.1% Triton X-100 for 10 minutes, and blocked with 5% bovine serum albumin (BSA) for 30 minutes. They were then incubated with a primary antibody against LC3 overnight at 4°C, followed by a fluorescein isothiocyanate (FITC)-conjugated secondary antibody for 1 hour at room temperature. Nuclei were stained with DAPI for 5 minutes. The number of LC3 puncta per cell was counted under a confocal laser scanning microscope (at least 50 cells per group) [4]
2. Bacterial susceptibility test (broth microdilution method): Serial two-fold dilutions of Clarithromycin (0.001-128 μg/mL) were prepared in Mueller-Hinton broth (for Gram-positive/negative bacteria) or Middlebrook 7H9 broth (for MAC). Bacterial suspensions were adjusted to a concentration of 5×10⁵ CFU/mL (for fast-growing bacteria) or 1×10⁴ CFU/mL (for MAC). 100 μL of the bacterial suspension was added to each well of a 96-well microtiter plate containing 100 μL of the drug dilution. The plates were incubated at 37°C (aerobic for Gram-positive/negative bacteria, 5% CO₂ for Haemophilus spp., anaerobic with 5% CO₂ for MAC) for 16-24 hours (fast-growing bacteria) or 7-10 days (MAC). The minimum inhibitory concentration (MIC) was defined as the lowest concentration of Clarithromycin that inhibited visible bacterial growth [1]

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.

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1. Beige mouse model of MAC infection and drug treatment: Male beige mice (C57BL/6J-bg/bg) aged 8-10 weeks were used. MAC strain 101 was cultured in Middlebrook 7H9 broth supplemented with 10% oleic acid-albumin-dextrose-catalase (OADC) until the mid-log phase. The bacterial suspension was centrifuged, washed twice with phosphate-buffered saline (PBS), and resuspended in PBS to a concentration of 1×10⁸ CFU/mL. Each mouse was infected via the lateral tail vein with 0.1 mL of the bacterial suspension (1×10⁷ CFU/mouse). One day post-infection, mice were randomly assigned to three groups (n=6 per group): (1) Vehicle control group: Oral gavage of 0.5% carboxymethylcellulose (CMC) solution (0.2 mL/mouse) once daily; (2) Low-dose Clarithromycin group: Oral gavage of Clarithromycin (100 mg/kg) dissolved in 0.5% CMC once daily; (3) High-dose Clarithromycin group: Oral gavage of Clarithromycin (200 mg/kg) dissolved in 0.5% CMC once daily. Treatment was continued for 21 consecutive days. During the treatment period, mouse body weight was measured every 3 days to monitor general health. At the end of treatment, mice were euthanized by CO₂ inhalation. The spleen and liver were removed, weighed, and homogenized in PBS (10% w/v) using a tissue homogenizer. Serial 10-fold dilutions of the homogenates were prepared, and 100 μL of each dilution was plated on Middlebrook 7H10 agar supplemented with OADC. The agar plates were incubated at 37°C in 5% CO₂ for 14 days, and the number of CFU was counted. The log₁₀ CFU per gram of tissue was calculated for each mouse [5]
2. Rat tissue distribution study: Male Sprague-Dawley rats (250-300 g) were fasted for 12 hours before administration, with free access to water. Clarithromycin was suspended in 0.5% CMC and administered by oral gavage at a dose of 20 mg/kg. At different time points (0.5, 1, 2, 4, 6, 8, 12 hours) after administration, 3 rats per time point were euthanized. Blood samples were collected via cardiac puncture, centrifuged at 3000 × g for 10 minutes to obtain plasma. Tissues (lung, tonsil, prostate, liver, kidney) were harvested, rinsed with cold PBS, blotted dry, and weighed. Tissue homogenates (10% w/v) were prepared in PBS. The concentrations of Clarithromycin in plasma and tissue homogenates were determined by high-performance liquid chromatography (HPLC) with ultraviolet detection. The mobile phase consisted of acetonitrile:0.05 M potassium dihydrogen phosphate (45:55, v/v), and the detection wavelength was 210 nm. Pharmacokinetic parameters (Cmax, Tmax, t₁/₂) and tissue/plasma concentration ratios were calculated [1]
.

Absorption, Distribution and Excretion
Clarithromycin is well absorbed, acid-resistant, and can be taken with food. After taking a 250 mg tablet every 12 hours, approximately 20% of the dose is excreted in the urine as clarithromycin; after taking a 500 mg tablet every 12 hours, the urinary excretion of clarithromycin is slightly higher, approximately 30%. Limited data are available on the distribution of clarithromycin in the human body. Clarithromycin and 14-hydroxyclarithromycin appear to be distributed in most body tissues and fluids. Due to higher intracellular concentrations, tissue concentrations are higher than serum concentrations. High concentrations of clarithromycin have been detected in tissue samples from patients who have undergone surgery. Reports indicate that patients who received 250-500 mg of clarithromycin orally every 12 hours for 3 days prior to surgery reached peak clarithromycin concentrations in the lungs, tonsils, and nasal mucosa 4 hours after administration, with average concentrations of 13.5-17.5, 5.3-6.5, and 5.9-8.3 mg/kg, respectively. However, studies suggest that these data may overestimate tissue concentrations of clarithromycin because microbial assays cannot distinguish between the parent drug and its active metabolites. In children receiving clarithromycin suspension for otitis media at a dose of 7.5 mg/kg every 12 hours for 5 doses, peak concentrations of clarithromycin and 14-hydroxyclarithromycin in the middle ear effusion were 2.5 and 1.3 μg/mL, respectively. Concomitant serum concentrations were 1.7 and 0.8 μg/mL, respectively. Animal studies have shown that administration of radiolabeled clarithromycin or erythromycin resulted in higher and more sustained activity of clarithromycin in various body tissues, particularly the lungs.
Clarithromycin is rapidly absorbed in the gastrointestinal tract after oral administration; its gastrointestinal absorption rate is higher than that of erythromycin.
Clarithromycin is eliminated via renal and non-renal routes.
In healthy men, after a single oral dose of 250 mg of radiolabeled clarithromycin, approximately 38% of the dose (18% of which is clarithromycin) is excreted in the urine within 5 days, and 40% of the dose (4% of which is clarithromycin) is excreted in the feces. With oral clarithromycin tablets, taken at 250 or 500 mg every 12 hours, approximately 20% or 30% of the dose is excreted unchanged in the urine within 12 hours. With oral clarithromycin suspension, taken at 250 mg every 12 hours, approximately 40% of the administered dose is excreted unchanged in the urine. The major metabolite of clarithromycin is 14-hydroxyclarithromycin, which accounts for approximately 10-15% of the dose after taking 250 or 500 mg of clarithromycin tablets in the urine. For more complete data on the absorption, distribution, and excretion of clarithromycins (6 in total), please visit the HSDB record page. Metabolism/Metabolites Hepatic Metabolism - Primarily metabolized by CYP3A4, leading to various drug interactions. The major metabolite of clarithromycin is 14-hydroxyclarithromycin, which accounts for approximately 10-15% of the dose in urine after administration of 250 or 500 mg clarithromycin tablets. Clarithromycin is extensively metabolized in the liver, primarily through oxidative N-demethylation and 14-hydroxylation; the glycosyl moiety of clarithromycin is also subject to minor hydrolysis in the stomach. Although at least 7 clarithromycin metabolites have been identified, 14-hydroxyclarithromycin is the major serum metabolite and the only one with significant antibacterial activity. Both the R- and S-epimers of 14-hydroxyclarithromycin can be generated in vivo, but the R-epimer is more abundant and exhibits stronger antibacterial activity. Clarithromycin metabolism appears to be saturated, as the amount of 14-hydroxyclarithromycin produced after taking 800 mg of the parent drug is only slightly higher than that produced after taking 250 mg of the parent drug. Following a single oral dose of 250 mg of radiolabeled clarithromycin in healthy men, approximately 38% of the dose (18% clarithromycin) is excreted in the urine within 5 days, and 40% (4% clarithromycin) is excreted in the feces. The major metabolite found in the urine is 14-hydroxyclarithromycin, accounting for approximately 10-15% of the dose after taking 250 or 500 mg clarithromycin tablets. Biological Half-Life: 3-4 hours. Following a single oral dose of 250 mg or 1.2 g of a standard clarithromycin tablet in healthy men, the average elimination half-life is 4 hours and 11 hours, respectively. It has been reported that when clarithromycin is administered multiple times every 12 hours, the elimination half-life increases from 3–4 hours after taking 250 mg (conventional tablets) every 12 hours to 5–7 hours after taking 500 mg every 8–12 hours; the half-life of 14-hydroxyclarithromycin increases from 5–6 hours at a 250 mg dose to 7–9 hours at a 500 mg dose. When clarithromycin is administered as an oral suspension, the elimination half-life of the drug and its 14-hydroxy metabolite appears to be similar to the half-life observed upon reaching steady state after taking an equivalent dose of clarithromycin tablets.

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1. Oral Absorption: In healthy volunteers, clarithromycin (500 mg) is well absorbed after a single oral dose, with a bioavailability of approximately 50% (range: 45%–55%). Food intake slightly delays the time to reach peak plasma concentration (Tmax) (from 1.2 hours to 2.1 hours), but does not significantly affect the area under the plasma concentration-time curve (AUC) or peak plasma concentration (Cmax, approximately 2.8 μg/mL) [1]
2. Plasma protein binding rate: The plasma protein binding rate of clarithromycin is concentration-dependent. At plasma concentrations of 0.1–2 μg/mL (therapeutic range), the binding rate is 70%–80%; at concentrations >10 μg/mL, the binding rate decreases to 40%–50% due to saturation of binding sites [1]
3. Tissue distribution: Clarithromycin has a wide tissue distribution. In the human body, the concentration of clarithromycin in lung tissue, sinus mucosa, tonsil tissue, and prostate tissue is 3–10 times higher than the plasma concentration. For example, the lung tissue concentration in patients with pneumonia can reach 8.5 μg/g, while the plasma concentration is 1.1 μg/mL. The drug can also penetrate into phagocytes (neutrophils, macrophages), with an intracellular/extracellular concentration ratio of 15-20 [1]
4. Metabolism: Clarithromycin is mainly metabolized in the liver by cytochrome P450 3A4 (CYP3A4) to produce its main active metabolite, 14-hydroxyclarithromycin. This metabolite has antibacterial activity (approximately 50% of the activity against Gram-positive bacteria) and a longer half-life than the parent drug (t₁/₂: 6-8 hours vs. 3-4 hours). Approximately 20%-30% of the oral dose is converted to 14-hydroxyclarithromycin [1,2]
5. Elimination: After oral administration, clarithromycin and its metabolites are mainly eliminated via feces and urine. About 40%-50% of the dose is excreted in feces (mainly in the form of the original drug) and 20%-30% is excreted in urine (10%-15% is the original drug and 10%-15% is 14-hydroxyclarithromycin). The plasma half-life (t₁/₂) of the parent drug in healthy adults is 3-4 hours; after multiple daily administration (500 mg twice daily), the half-life increases to 5-7 hours due to drug accumulation [1]
6. Effects on drug-metabolizing enzymes:Clarithromycin is a potent inhibitor of CYP3A4 in vitro (IC50 = 8.2 μM) and in vivo, and can increase the plasma concentration of drugs metabolized by CYP3A4 (e.g., warfarin, cyclosporine) [2]
.

Hepatotoxicity
Clarithromycin, like other macrolide antibiotics, is associated with acute, transient, and usually asymptomatic elevations in serum transaminase levels, occurring in 1% to 2% of patients on short-term treatment and slightly more frequently in patients on long-term treatment. Asymptomatic elevations of serum enzymes are particularly common in elderly patients taking higher doses of clarithromycin. Clarithromycin can also cause acute, clinically significant liver injury with jaundice, estimated at 3.8 cases per 100,000 prescriptions. Liver injury usually occurs within 1 to 3 weeks of starting treatment, but may also occur after discontinuation of clarithromycin. The pattern of liver enzyme elevation varies, but the resulting hepatitis is usually cholestatic hepatitis and can have a prolonged course (Case 1). There are currently no consistent reports of signs and symptoms of allergic reactions. Cholestatic hepatitis is the most typical manifestation of clarithromycin-induced liver injury, but rare cases of hepatocellular injury and sudden onset have also been reported. These cases of hepatocellular injury tend to be more severe and can lead to acute liver failure. However, in most cases, recovery occurs within 4 to 8 weeks after discontinuation of the drug. The typical incubation period, clinical presentation, and course of cholestatic hepatitis caused by clarithromycin are similar to those of other macrolide antibiotics.
Probability Score: B (Very likely to cause clinically significant liver damage).

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Use during pregnancy and lactation
◉ Overview of use during lactation
Because clarithromycin is present in low concentrations in breast milk and can be safely administered directly to infants, it is safe for breastfeeding women to use. Small amounts of clarithromycin in breast milk are unlikely to have adverse effects on the infant. Closely monitor the infant's gut microbiota for potential impacts such as diarrhea, candidiasis (thrush, diaper rash). Unproven epidemiological evidence suggests that maternal use of macrolide antibiotics during the first two weeks of breastfeeding may increase the risk of hypertrophic pyloric stenosis in infants, but this has been challenged by other studies.
◉ Impact of Breastfeeding on Infants
A cohort study of infants diagnosed with hypertrophic pyloric stenosis found that mothers of affected infants were 2.3 to 3 times more likely to have taken macrolide antibiotics within 90 days postpartum than other infants. Stratified analysis of the infants showed an odds ratio of 10 for girls and 2 for boys. All affected infants' mothers breastfed. The majority of macrolide prescriptions were erythromycin, with clarithromycin accounting for only 1.7%. However, the authors did not specify which macrolide antibiotics the affected infants' mothers took.
A study comparing infants breastfed by mothers taking amoxicillin with infants breastfed by mothers taking macrolide antibiotics found no cases of pyloric stenosis in either group. However, most infants exposed to macrolide antibiotics through breast milk were exposed to roxithromycin. Of the 55 infants exposed to macrolide antibiotics, only 6 were exposed to clarithromycin. Infants exposed to macrolide antibiotics experienced adverse reactions in 12.7% of cases, a rate similar to that of infants exposed to amoxicillin. Adverse reactions included rash, diarrhea, loss of appetite, and drowsiness. A retrospective database study in Denmark analyzing 15 years of data found that infants breastfed by mothers who took macrolide antibiotics within 13 days postpartum had a 3.5-fold increased risk of developing hypertrophic pyloric stenosis, but this risk was not observed after subsequent use. The proportion of breastfed infants is unknown but likely high. The proportion of women taking each macrolide antibiotic was also not reported. Two meta-analyses failed to confirm an association between maternal use of macrolide antibiotics during lactation and infant hypertrophic pyloric stenosis. ◉ Effects on lactation and breast milk: As of the revision date, no relevant published information was found.

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Protein binding
~70% protein binding

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1. Cardiotoxicity (HERG channel inhibition): Clarithromycin inhibits HERG potassium channels in vitro (IC50 = 18.6 μM), which is associated with delayed repolarization of the human heart (QT interval prolongation). In healthy volunteers, oral administration of clarithromycin (500 mg twice daily) for 7 days resulted in a mean prolongation of the corrected QT interval (QTc) of 15–20 milliseconds. Patients with a history of heart disease (e.g., hypokalemia, heart failure) or who are taking other drugs that prolong the QT interval are at higher risk of QT interval prolongation [3].
2. Hepatotoxicity: In rare cases, administration of clarithromycin may lead to elevated serum transaminases (ALT, AST) and bilirubin. In a clinical study of 1,000 patients treated with clarithromycin (500 mg twice daily for 14 days), 2.3% of patients had ALT levels exceeding 3 times the upper limit of normal (ULN), and 1.1% had AST levels exceeding 3 times the ULN. Liver enzymes returned to normal within 2–4 weeks after discontinuation of the drug [1]. 3. Drug interactions: Because clarithromycin inhibits CYP3A4, it can increase the plasma concentration of CYP3A4 substrates when used in combination. For example, co-administration of clarithromycin (500 mg twice daily) with cyclosporine (5 mg/kg once daily) can increase the AUC of cyclosporine by 2.5 times, thereby increasing the risk of nephrotoxicity. Similarly, co-administration with warfarin can increase the international normalized ratio (INR) by 1.5–2.0 times, thereby increasing the risk of bleeding [1,2].
4. Gastrointestinal toxicity: The most common adverse reactions of clarithromycin are gastrointestinal symptoms, including nausea (8%–12%), diarrhea (6%–10%), abdominal pain (4%–6%), and vomiting (2%–4%). These symptoms are usually mild to moderate and can be relieved by continued treatment or discontinuation of the drug [1].
5. Plasma protein binding-related toxicity: Plasma protein binding of clarithromycin is concentration-dependent, and high doses (>1000 mg/day) may lead to increased free drug concentrations, which may increase the risk of adverse reactions such as headache and dizziness [1].

[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 may cause developmental toxicity depending on state or federal labeling requirements. Clarithromycin, the 6-O-methyl ether of erythromycin A, is a macrolide antibiotic used to treat respiratory, skin, and soft tissue infections. It is also used to eradicate Helicobacter pylori and treat peptic ulcers. Clarithromycin inhibits bacterial growth by interfering with bacterial protein synthesis. It is both an antibacterial agent and a protein synthesis inhibitor, as well as an environmental pollutant and exogenous substance. Clarithromycin is a prescription antibacterial drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of certain bacterial infections, such as community-acquired pneumonia, pharyngitis, and acute sinusitis. Clarithromycin is also FDA-approved for the prevention and treatment of Mycobacterium avium complex (MAC) infection, another type of bacterial infection. Community-acquired pneumonia is a bacterial respiratory disease, and disseminated MAC infection can also be an opportunistic infection (OI) in HIV-infected individuals. Opportunistic infections are those that are more common or more severe in people with weakened immune systems (such as HIV-infected individuals) than in people with healthy immune systems. Clarithromycin is a semi-synthetic macrolide antibiotic derived from erythromycin. It inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit. This binding inhibits peptidyl transferase activity and interferes with amino acid transport during translation and protein assembly. The bacteriostatic or bactericidal effect of clarithromycin depends on the pathogen and drug concentration. Clarithromycin is a macrolide antibacterial drug. Its mechanism of action is as a cytochrome P450 3A4 inhibitor, a cytochrome P450 3A inhibitor, and a P-glycoprotein inhibitor. Clarithromycin is a semi-synthetic macrolide antibiotic used to treat a variety of mild to moderate bacterial infections. Clarithromycin is associated with rare cases of acute liver injury, which can be severe or even fatal. Clarithromycin is a semi-synthetic 14-membered ring macrolide antibiotic. Clarithromycin binds to the 50S ribosomal subunit, inhibiting RNA-dependent protein synthesis in susceptible organisms. Studies have shown that clarithromycin can eradicate gastric mucosa-associated lymphoid tissue (MALT) lymphoma, possibly due to its eradication of tumorigenic Helicobacter pylori infection. This drug also acts as a biological response modifier, potentially inhibiting angiogenesis and tumor growth by altering growth factor expression. (NCI04)
A semi-synthetic macrolide antibiotic derived from erythromycin, effective against a variety of microorganisms. It inhibits bacterial protein synthesis by reversibly binding to the 50S ribosomal subunit. This inhibits the translocation of aminoacyltransfer RNA, thereby preventing peptide chain elongation.
See also: Clarithromycin lactobionate (active ingredient); Amoxicillin; Clarithromycin; Lansoprazole (ingredient); Amoxicillin; Clarithromycin; Vonoprazan fumarate (ingredient)...See more...

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Drug Indications
This product can be used as an alternative treatment for acute otitis media caused by Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae, especially suitable for patients with a history of type I penicillin allergy. In addition, this product can be used to treat pharyngitis and tonsillitis caused by susceptible Streptococcus pyogenes, as well as respiratory infections, including acute maxillary sinusitis, acute bacterial exacerbations of chronic bronchitis, mild to moderate community-acquired pneumonia, Legionnaires' disease, and pertussis. Other indications include the treatment of uncomplicated skin or soft tissue infections, Helicobacter pylori infection, duodenal ulcers, Bartonella infection, early Lyme disease, and encephalitis caused by Toxoplasma gondii (in HIV-infected patients, it needs to be used in combination with pyrimethamine). Clarithromycin can also reduce the incidence of cryptosporidiosis, prevent alpha-hemolytic (Viridans Streptococcus group) endocarditis, and can be used as primary prevention for Mycobacterium avium complex (MAC) bacteremia or disseminated infection (for adults, adolescents, and children with late-stage HIV infection). Clarithromycin, in combination with vonoprazan and amoxicillin, is used as a triple therapy for the treatment of Helicobacter pylori (H. pylori) infection in adults.
FDA Label
Treatment of Helicobacter pylori Infection
Treatment of Helicobacter pylori Infection

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Mechanism of Action
Clarithromycin is first metabolized to 14-hydroxyclarithromycin, which is active and synergistically acts with its parent compound. Like other macrolide antibiotics, clarithromycin penetrates the bacterial cell wall and reversibly binds to the V domain of the 23S ribosomal RNA of the 50S subunit of the bacterial ribosome, thereby blocking the translocation of aminoacyltransfer RNA and polypeptide synthesis. Clarithromycin also inhibits the hepatic microsomal CYP3A4 isoenzyme and P-glycoprotein (an energy-dependent drug efflux pump).
Clarithromycin generally has antibacterial activity, but may have bactericidal activity at high concentrations or against highly susceptible microorganisms. Bactericidal activity has been observed against Streptococcus pyogenes, Streptococcus pneumoniae, Haemophilus influenzae, and Chlamydia trachomatis. Clarithromycin inhibits protein synthesis in susceptible microorganisms by penetrating the cell wall and binding to the 50S ribosomal subunit, thereby inhibiting the translocation of aminoacyltransferRNA and suppressing polypeptide synthesis. The site of action of clarithromycin appears to be the same as that of erythromycin, clindamycin, lincomycin, and chloramphenicol.

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1. Classification and Mechanism of Action: Clarithromycin is a semi-synthetic macrolide antibiotic derived from erythromycin. Its antibacterial mechanism involves binding to the 50S subunit of the bacterial ribosome, interfering with the translocation step of peptide chain elongation, thereby inhibiting bacterial protein synthesis. This mechanism is antibacterial, but at high concentrations it has bactericidal effects on susceptible strains[1]
2. Treatment indications: Clarithromycin is approved for the treatment of a variety of bacterial infections, including: (1) Upper respiratory tract infections caused by Streptococcus pneumoniae, Haemophilus influenzae or Moraxella catarrhalis (sinusitis, pharyngitis, tonsillitis); (2) Lower respiratory tract infections caused by Streptococcus pneumoniae, Haemophilus influenzae, Legionella pneumophila or Mycoplasma pneumoniae (community-acquired pneumonia, acute exacerbation of chronic bronchitis); (3) Skin and soft tissue infections caused by Staphylococcus aureus or Streptococcus pyogenes; (4) Prevention and treatment of Mycobacterium avium complex (MAC) infection in immunocompromised patients (e.g., HIV-infected individuals)[1,5]
3. Resistance mechanisms: Bacterial resistance to clarithromycin is mainly generated through three mechanisms: (1) Methylation of 23S rRNA in the 50S ribosomal subunit (by erm (1) Gene encoding), reducing drug binding affinity; (2) Efflux pump overexpression (encoded by mef or msr gene), increasing drug efflux from bacterial cells; (3) 23S rRNA gene mutation, altering drug binding site [1]
4. Role in colorectal cancer: Clarithromycin inhibits autophagy in colorectal cancer cells by disrupting the interaction between HERG1 potassium channel and PI3K, thereby leading to downregulation of the PI3K/Akt/mTOR signaling pathway. In preclinical models, autophagy inhibition enhanced the sensitivity of colorectal cancer cells to chemotherapeutic drugs (e.g., 5-fluorouracil), suggesting its potential as an adjuvant therapy [4]
5. Advantages of clarithromycin: Compared with its parent drug erythromycin, clarithromycin has several advantages: (1) higher oral bioavailability (50% vs. 35%); (2) longer half-life (3-4 hours vs. 1-2 hours), allowing for twice-daily dosing; (3) reduced gastrointestinal toxicity (due to reduced affinity for motilin receptors); (4) enhanced activity against atypical pathogens (mycoplasma, chlamydia, Legionella) and the Mycobacterium avium complex (MAC) [1]
.

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.)