| Size | Price | Stock | Qty |
|---|---|---|---|
| 50mg |
|
||
| 100mg |
|
||
| 250mg | |||
| 500mg | |||
| Other Sizes |
Purity: ≥98%
Clevudine (L-FMAU; L FMAU; Levovir and Revovir) is a potent antiviral drug approved in South Korea and the Philippines for the treatment of hepatitis B (HBV) infections with EC50 0.1 μM in HepG2 2.2.15 cells as well as EBV. Numerous cell lines, such as MT2, CEM, H1, HepG2 2.2.15, and bone marrow progenitor cells, exhibit minimal cytotoxicity when exposed to clevodine exposure. In cells, clevudine is broken down into its monophosphate, then into its di- and triphosphates by cellular thymidine kinase and deoxycytidine kinase.
| Targets |
RNA polymerase; DNA polymerase
Clevudine (L-FMAU) targets hepatitis B virus (HBV) reverse transcriptase (DNA polymerase) (EC50=0.004~0.01 μM in HepG2.2.15 cells)[2] Clevudine (L-FMAU) inhibits duck hepatitis B virus (DHBV) DNA polymerase (EC50=0.002 μM in primary duck hepatocytes)[5] |
|---|---|
| ln Vitro |
Clenudine is a potent antiviral drug against both EBV and HBV (EC50 0.1 μM in HepG2 2.2.15 cells), with minimal cytotoxicity in MT2, CEM, H1, HepG2 2.2.15, and bone marrow progenitor cells. The cellular thymidine kinase and deoxycytidine kinase break down clevudine into its monophosphate, which is then converted to the di- and triphosphate in cells. The mechanism of action of clevudine is specific to the synthesis of viral DNA; its triphosphate prevents HBV DNA synthesis in a dose-dependent manner without entering the DNA or causing chain termination.[1] The metabolites of these analogs, diphosphate and triphosphate, increase in concentration when clevudine is administered. The D-configuration anomer of clevudine monophosphate (L-FMAUMP) is a better substrate.[2] In cell culture, levudine is easily phosphorylated to the corresponding 5'-triphosphate form of the compound, which affects levudine's mode of action.[3]
Anti-HBV activity: In HepG2.2.15 cells (stable HBV-expressing), treatment with 0.1 μM Clevudine for 72 hours reduced HBV DNA levels by 99%; at 0.01 μM, HBsAg and HBeAg secretion decreased by 68% and 75%, respectively[2] - Anti-DHBV activity: In primary duck hepatocytes, 0.002 μM Clevudine inhibited 50% of DHBV DNA synthesis, with an inhibition rate of 98% at 0.1 μM, and no obvious cytotoxicity[5] - Genotype coverage: Potent inhibition against HBV genotypes A, B, C, and D, with EC50 values ranging from 0.003~0.012 μM, no genotypic selectivity[3] - Low cytotoxicity: CC50 values were >100 μM in primary human hepatocytes, HepG2, and Hep3B cells, with a therapeutic index (CC50/EC50) >10000[2] - No activity against other viruses: EC50 values for HCV, HIV-1, and HSV-1/2 were all >100 μM, with no cross-inhibition[1] - Mechanism verification: Metabolized to the triphosphate derivative (L-FMAU-TP), which competitively incorporates into HBV DNA strands, leading to chain termination and blocking viral genome replication[4] |
| ln Vivo |
Clenudine is a potent antiviral drug against both EBV and HBV (EC50 0.1 μM in HepG2 2.2.15 cells), with minimal cytotoxicity in MT2, CEM, H1, HepG2 2.2.15, and bone marrow progenitor cells. The cellular thymidine kinase and deoxycytidine kinase break down clevudine into its monophosphate, which is then converted to the di- and triphosphate in cells. The mechanism of action of clevudine is specific to the synthesis of viral DNA; its triphosphate prevents HBV DNA synthesis in a dose-dependent manner without entering the DNA or causing chain termination.[1] The metabolites of these analogs, diphosphate and triphosphate, increase in concentration when clevudine is administered. The D-configuration anomer of clevudine monophosphate (L-FMAUMP) is a better substrate.[2] In cell culture, levudine is easily phosphorylated to the corresponding 5'-triphosphate form of the compound, which affects levudine's mode of action.[3]
Duck DHBV model (DHBV-infected ducklings): Oral administration of Clevudine 10 mg/kg once daily for 14 days reduced serum DHBV DNA by 4.2 log10 copies/mL from baseline, with sustained inhibition of 3.8 log10 copies/mL 2 weeks after drug withdrawal[5] - Chimpanzee HBV model (HBV-infected chimpanzees): Oral Clevudine 3 mg/kg once daily for 28 days decreased serum HBV DNA by 5.0 log10 IU/mL and HBsAg by 30%, with no viral rebound[3] - Mouse HBV model (hydrodynamic plasmid injection): Intraperitoneal injection of Clevudine 20 mg/kg once daily for 7 days reduced hepatic HBV DNA by 90% and serum HBV DNA by 85%[5] - Long-term efficacy: In duck DHBV model, continuous administration for 28 days maintained serum DHBV DNA below the detection limit, with a recurrence rate of only 10% 4 weeks after withdrawal, significantly lower than the lamivudine group (60%)[5] |
| Enzyme Assay |
HBV reverse transcriptase inhibition assay: Purified recombinant HBV reverse transcriptase was incubated with serial concentrations of Clevudine (0.001~10 μM) in a reaction system containing template-primer complexes for 30 minutes. Radiolabeled dNTP substrates were added, and the reaction was incubated at 37°C for 1 hour. DNA synthesis was detected by filter-binding assay. Results showed 50% enzyme activity inhibition at 0.005 μM, with concentration-dependent inhibition[4]
- DHBV DNA polymerase activity assay: Viral polymerase was extracted from DHBV-infected duck liver, incubated with different drug concentrations, and then DHBV genomic RNA template and dNTP substrates were added. After 2 hours of reaction, DNA products were detected by agarose gel electrophoresis. 0.002 μM Clevudine inhibited 50% polymerase activity, and complete blocking of DNA synthesis was observed at 1 μM[5] |
| Cell Assay |
HBV DNA inhibition assay: HepG2.2.15 cells were seeded in 6-well plates at 2×10⁵ cells/well, incubated for 24 hours, and then treated with serial concentrations of Clevudine (0.001~10 μM) for 72 hours. Intracellular HBV DNA was extracted and quantified by real-time PCR to calculate the viral load reduction ratio[2]
- Viral antigen secretion assay: After treating HepG2.2.15 cells with 0.001~1 μM Clevudine for 72 hours, cell supernatants were collected, and HBsAg and HBeAg levels were detected by ELISA to calculate the secretion inhibition rate[2] - Cytotoxicity assay (MTT method): Primary human hepatocytes and HepG2 cells were seeded in 96-well plates at 1×10⁴ cells/well, incubated for 24 hours, and then treated with 0.1~200 μM Clevudine for 72 hours. MTT reagent was added, incubated for 4 hours, and absorbance at 570 nm was measured to calculate CC50 values[2] - Chain termination verification assay: HepG2.2.15 cells were treated with 0.1 μM Clevudine for 48 hours, intracellular HBV DNA was extracted, and DNA strand length was analyzed by Southern blot. Short-chain DNA fragments were observed in the drug-treated group, confirming chain extension termination[4] |
| Animal Protocol |
Duck DHBV model (DHBV-infected ducklings): 1-day-old ducklings were intravenously injected with DHBV-positive serum (10⁶ copies/duck), and drug administration started on day 3 post-infection. Clevudine was dissolved in normal saline to prepare a 1 mg/mL solution, administered orally at 10 mg/kg once daily for 14~28 days. Serum was collected every 3 days, and DHBV DNA load was detected by real-time PCR[5] - Chimpanzee HBV model (HBV-infected chimpanzees): Adult chimpanzees were intravenously inoculated with HBV wild-type strain (10⁷ IU), and drug administration started when serum HBV DNA was positive. The drug was dissolved in distilled water, administered orally at 3 mg/kg once daily for 28 days. Serum was collected weekly to detect HBV DNA, HBsAg, and liver function indices[3] - Mouse HBV model (hydrodynamic injection): BALB/c mice were hydrodynamically injected with HBV expression plasmid (10 μg/mouse) via the tail vein, and drug administration started on day 2 post-injection. Clevudine was dissolved in normal saline, administered intraperitoneally at 20 mg/kg once daily for 7 days. Mice were sacrificed at the end of the experiment, and hepatic tissue and serum were collected to detect HBV DNA levels[5] |
| ADME/Pharmacokinetics |
Absorption: The oral bioavailability in rats is 70%~80%; after a single oral dose of 10 mg/kg, the peak plasma concentration (Cmax) is 1.2 μg/mL and the time to peak concentration (Tmax) is 1.5 hours [3]
- Distribution: The drug concentration is highest in the liver. After oral administration of 10 mg/kg, the drug concentration in the liver can reach 8.5 times the plasma concentration; followed by the kidneys and spleen. The drug concentration in the brain tissue is extremely low (<1% of the plasma concentration) [3] - Metabolism: Very little metabolism occurs in the body. It mainly exists in the original form; a small amount of the drug is converted into a triphosphate derivative (L-FMAU-TP) in the liver. This derivative is the active form with a half-life of >24 hours [4] - Excretion: Within 72 hours after administration to rats, the amount excreted in urine accounts for 65%~70% of the administered dose, the amount excreted in feces accounts for 10%~15%, and the original drug accounts for more than 90% of the total excretion [3] - Half-life: The elimination half-life (t1/2) after oral administration in rats was 12-15 hours; the t1/2 after intravenous injection was 10-12 hours [3] - Plasma protein binding rate: In vitro experiments showed that the plasma protein binding rate of this drug in humans, rats and dogs was <10%, with no significant species differences [3] |
| Toxicity/Toxicokinetics |
Nephrotoxicity: After long-term administration (30 mg/kg, orally, once daily for 6 months) to rats, vacuolar degeneration of renal tubular epithelial cells occurred in approximately 30% of rats; no significant kidney damage was observed at a dose of 10 mg/kg [3] - Hepatotoxicity: After long-term administration (3 mg/kg, 28 days), no significant increase in serum ALT and AST levels was observed in chimpanzees, and no abnormalities were found in liver histopathological examination [3] - Hematologic toxicity: After oral administration (50 mg/kg, 30 days), no significant changes were observed in white blood cell, red blood cell, or platelet counts in mice, and no bone marrow suppression was observed [5] - Median lethal dose (LD50): Oral LD50 in mice > 500 mg/kg, intravenous LD50 > 300 mg/kg [1] - Drug interaction: In vitro experiments showed that the drug does not inhibit or induce cytochrome P450 enzymes (CYP1A2, CYP2C9, CYP3A4, etc.). No pharmacokinetic interactions were observed when used in combination with lamivudine or adefovir dipivoxil [3]
|
| References | |
| Additional Infomation |
Clavudine is a pyrimidine 2'-deoxynucleoside. Clavudine is a synthetic pyrimidine analog with anti-hepatitis B virus (HBV) activity. Intracellularly, clavidine is phosphorylated to its active metabolites, clavidine monophosphate and clavidine triphosphate. The triphosphate metabolite competes with thymidine for incorporation into viral DNA, leading to DNA chain termination and inhibition of HBV DNA polymerase (reverse transcriptase). Clavudine has a long half-life and significantly reduces covalently closed circular DNA (cccDNA), thus reducing the likelihood of relapse after discontinuation of the drug. Drug Indications It has been studied for the treatment of viral hepatitis (hepatitis B). Mechanism of Action: Clavudine is a pyrimidine nucleoside analog. After oral administration, the drug is phosphorylated in cells to form a triphosphate derivative (L-FMAU-TP), which competitively binds to the reverse transcriptase of hepatitis B virus (HBV) and is incorporated into the viral DNA chain, causing chain termination and thus blocking HBV genome replication [4]
- Indications: Used to treat chronic hepatitis B, it can significantly reduce serum HBV DNA load and improve liver function [3] - Drug resistance: After continuous in vitro culture for 6 months, no drug-resistant mutant strains were screened in HepG2.2.15 cells; clinical studies showed that the drug resistance rate after 1 year of treatment was <5%, which was significantly lower than that of lamivudine [3] - Advantages of administration: Oral administration once a day, low dose (adult recommended dose 30 mg/day), high patient compliance [3] |
| Molecular Formula |
C10H13FN2O5
|
|
|---|---|---|
| Molecular Weight |
260.22
|
|
| Exact Mass |
260.081
|
|
| Elemental Analysis |
C, 46.16; H, 5.04; F, 7.30; N, 10.77; O, 30.74
|
|
| CAS # |
163252-36-6
|
|
| Related CAS # |
|
|
| PubChem CID |
73115
|
|
| Appearance |
White to off-white solid powder
|
|
| Density |
1.55g/cm3
|
|
| Melting Point |
184-185°
|
|
| Index of Refraction |
1.592
|
|
| LogP |
-0.9
|
|
| Hydrogen Bond Donor Count |
3
|
|
| Hydrogen Bond Acceptor Count |
6
|
|
| Rotatable Bond Count |
2
|
|
| Heavy Atom Count |
18
|
|
| Complexity |
413
|
|
| Defined Atom Stereocenter Count |
4
|
|
| SMILES |
F[C@@]1([H])[C@@]([H])(N2C(N([H])C(C(C([H])([H])[H])=C2[H])=O)=O)O[C@@]([H])(C([H])([H])O[H])[C@]1([H])O[H]
|
|
| InChi Key |
GBBJCSTXCAQSSJ-XQXXSGGOSA-N
|
|
| InChi Code |
InChI=1S/C10H13FN2O5/c1-4-2-13(10(17)12-8(4)16)9-6(11)7(15)5(3-14)18-9/h2,5-7,9,14-15H,3H2,1H3,(H,12,16,17)/t5-,6+,7-,9-/m0/s1
|
|
| Chemical Name |
1-[(2S,3R,4S,5S)-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione
|
|
| Synonyms |
|
|
| HS Tariff Code |
2934.99.9001
|
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
|
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
|
|||
|---|---|---|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (9.61 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (9.61 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (9.61 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.8429 mL | 19.2145 mL | 38.4290 mL | |
| 5 mM | 0.7686 mL | 3.8429 mL | 7.6858 mL | |
| 10 mM | 0.3843 mL | 1.9215 mL | 3.8429 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT04891302 | Completed | Drug: Clevudine Drug: Placebo |
COVID-19 | Bukwang Pharmaceutical | March 19, 2021 | Phase 2 |
| NCT01192854 | Completed | Drug: Clevudine Drug: Adefovir |
Chronic Hepatitis B | Eisai Co., Ltd. | February 2010 | Phase 3 |
| NCT00558818 | Completed | Drug: Clevudine | Chronic Hepatitis B | Bukwang Pharmaceutical | June 2007 | Phase 4 |
| NCT04347915 | Completed | Drug: Clevudine Drug: Placebo |
COVID-19 | Bukwang Pharmaceutical | May 26, 2020 | Phase 2 |
| NCT00558493 | Completed | Drug: Clevudine | Chronic Hepatitis B | Bukwang Pharmaceutical | November 2007 | Phase 4 |
|
|
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
COA
