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

克拉霉素具有类似的浓度依赖性阻断，IC50 为 45.7 μM [3]。 24 小时后，Clarithromycin 会导致所有细胞系（特别是 HCT116 细胞）中形成大量胞质内空泡。长期克拉霉素（40、80 和 160 μM）治疗会改变结直肠癌 (CRC) 中的细胞增殖并引发细胞凋亡。克拉霉素重新给予细胞会增加对细胞增殖的抑制。孵育 48 小时后重新添加 160 μM 克拉霉素会导致细胞增殖在 72 小时停止。在 LS174T 细胞中观察到类似的效果[4]。克拉霉素（80 和 160 μM；48 小时）以剂量和时间依赖性方式显着增加 LC3-II/LC3-I 比率，在治疗 24 小时时达到峰值。这种效应与 p62/SQSTM1 的减少有关[4]。

200 mg/kg 的克拉霉素在四项体内测试中均具有活性[5]。在传播性鸟分枝杆菌复合物（MAC）感染的米色（C57BL/6J bgj/bgj）小鼠模型中评估了克拉霉素单独和与其他抗分枝杆菌药物联合的活性。对感染约10（7）只活MAC的小鼠进行剂量反应实验，每天通过强饲法给予克拉霉素50、100、200或300mg/kg体重。在50、100和200mg/kg的治疗中，脾脏和肝脏细胞计数出现了剂量相关的减少。200和300mg/kg治疗之间的细胞计数差异并不显著。发现200mg/kg体重的克拉霉素对另外三种MAC分离株具有活性（通过肉汤稀释，分离株的MIC范围为1至4微克/ml）。200 mg/kg的克拉霉素与阿米卡星、乙胺丁醇、替马沙星或利福平联合使用，其活性没有超过单独使用克拉霉素的活性。克拉霉素与氯法齐明或利福布汀联合使用导致活性增加，超过了单独使用克拉霉素的效果。克拉霉素与氯法齐明或利福布汀的联合应用应考虑用于评估治疗人类MAC感染的效果。

克拉霉素（Cla）结合试验[4]
通过在转染了hERG1和不同hERG1突变体的正常人胚胎肾（HEK）293细胞上使用荧光标记的11-O-{3-[（7-硝基-2,1,3-苯并恶二唑-4-基）氨基]丙基}-6-O-甲基红霉素A（简称：11-NBD-Cla）来评估Cla与hERG1的结合。在完全培养基中，以1×104个细胞/孔的速度将细胞接种在96孔黑色测定板上。24小时后，在37°C下用10µM 11 NBD Cla处理细胞30分钟。在室温下用磷酸盐缓冲盐水（PBS）短暂洗涤后，立即用Synergy H1微孔板读数器测量荧光强度（激发/发射463/536nm）。然后将细胞在0.5%Triton X-100中在冰上裂解15分钟，并通过Bio-Rad蛋白质测定法测定蛋白质浓度。在减去从HEK293 MOCK细胞获得的值后，荧光强度根据总蛋白质含量进行归一化。所获得的数据在用不同突变体转染的HEK293细胞中的相对hERG1表达上进行了归一化，如参考文献48所示。因此，在图3e中，获得的结果被称为“相对于MOCK细胞，11NBD-Cla荧光增加”。

细胞增殖测定[4]
细胞类型： HCT116 细胞
测试浓度： 40、80 和 160 µM
孵育时间： 24、48、72小时
实验结果：减少HCT116细胞增殖，但并未完全消除。

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蛋白质印迹分析[4]
细胞类型： HCT116 细胞
测试浓度： 80 和 160 µM
孵育持续时间：4、24、48小时
实验结果：48小时时观察到LC3-II的减少和p62/SQSTM1的重新增加（小时）治疗。

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

182.91

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)

配方 1 中的溶解度: 2.5 mg/mL (3.34 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 悬浮液；超声助溶。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: 2.5 mg/mL (3.34 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 悬浊液; 超声助溶。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (3.34 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
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7、 以上所有助溶剂都可在 Invivochem.cn网站购买。