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Vinorelbine (KW-2307; Nor-5'-anhydrovinblastine) is a potent antimitotic agent and a semisynthetic vinca alkaloid derived from the leaves of the periwinkle plant (Vinca rosea) used for the treatment for some types of cancer, including breast cancer and non-small cell lung cancer. Vinorelbine blocks cell cycle progression in mitosis with IC50 of 3.8 nM, which is only slightly higher than the IC50 value for inhibition of proliferation, indicating that mitotic block is a major contributor to antiproliferative action.
Physicochemical Properties
| Molecular Formula | C45H54N4O8 |
| Molecular Weight | 778.9323 |
| Exact Mass | 778.394 |
| CAS # | 71486-22-1 |
| Related CAS # | 125317-39-7 (tartrate);105661-07-2 (tartrate 1:1);71486-22-1; |
| PubChem CID | 5311497 |
| Appearance | Typically exists as solid at room temperature |
| Density | 1.4±0.1 g/cm3 |
| Melting Point | 181-183 |
| Index of Refraction | 1.676 |
| LogP | 4.69 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 11 |
| Rotatable Bond Count | 10 |
| Heavy Atom Count | 57 |
| Complexity | 1690 |
| Defined Atom Stereocenter Count | 8 |
| SMILES | O(C(C([H])([H])[H])=O)[C@@]1([H])[C@](C(=O)OC([H])([H])[H])([C@@]2([H])[C@@]3(C4=C([H])C([C@]5(C(=O)OC([H])([H])[H])C6=C(C7=C([H])C([H])=C([H])C([H])=C7N6[H])C([H])([H])N6C([H])([H])C(C([H])([H])C([H])([H])[H])=C([H])[C@]([H])(C6([H])[H])C5([H])[H])=C(C([H])=C4N2C([H])([H])[H])OC([H])([H])[H])C([H])([H])C([H])([H])N2C([H])([H])C([H])=C([H])[C@]1(C([H])([H])C([H])([H])[H])[C@]23[H])O[H] |
| InChi Key | GBABOYUKABKIAF-IELIFDKJSA-N |
| InChi Code | InChI=1S/C45H54N4O8/c1-8-27-19-28-22-44(40(51)55-6,36-30(25-48(23-27)24-28)29-13-10-11-14-33(29)46-36)32-20-31-34(21-35(32)54-5)47(4)38-43(31)16-18-49-17-12-15-42(9-2,37(43)49)39(57-26(3)50)45(38,53)41(52)56-7/h10-15,19-21,28,37-39,46,53H,8-9,16-18,22-25H2,1-7H3/t28-,37-,38+,39+,42+,43+,44-,45-/m0/s1 |
| Chemical Name | methyl (1R,9R,10S,11R,12R,19R)-11-acetyloxy-12-ethyl-4-[(12S,14R)-16-ethyl-12-methoxycarbonyl-1,10-diazatetracyclo[12.3.1.03,11.04,9]octadeca-3(11),4,6,8,15-pentaen-12-yl]-10-hydroxy-5-methoxy-8-methyl-8,16-diazapentacyclo[10.6.1.01,9.02,7.016,19]nonadeca-2,4,6,13-tetraene-10-carboxylate |
| 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) |
Biological Activity
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| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Vinorelbine is rapidly absorbed with peak serum concentration reached within 2 hours. Vinorelbine is highly bound to platelets and lymphocytes and is also bound to alpha 1-acid glycoprotein, albumin, and lipoproteins. Vinorelbine undergoes substantial hepatic elimination in humans, with large amounts recovered in feces after intravenous administration to humans. Urinary excretion of unchanged drug accounts for less than 20% of an intravenous dose, with fecal elimination accounting for an additional 30% to 60%. After intravenous administration of radioactive vinorelbine, approximately 18% and 46% of administered radioactivity was recovered in urine and feces, respectively. The volume of distribution is large, indicating extensive extravascular distribution. The steady-state volume of distribution values range from 25.4 to 40.1 L/kg, according to one study. Widely distributed, with highest amounts found in elimination organs such as liver and kidneys, minimal in heart and brain. The plasma clearance of vinorelbine is high, approaching the same as hepatic blood flow in humans, and its volume of distribution is large, indicating extensive extravascular distribution. In comparison to vinblastine or vincristine. The clearance was found to be in the range of 0.29-1./26 L/ per kg in 4 clinical trials of patients receiving 30 mg/m2 of vinorelbine. The initial rapid decline in plasma vinorelbine concentration following iv administration represents distribution of the drug to peripheral compartments. Following administration of vinorelbine 30 mg/sq m iv over 15-20 minutes, a steady-state volume of distribution of 25.4-40.1 L/kg has been reported. Vinorelbine demonstrates high binding to human platelets and lymphocytes. Binding of the drug to plasma constituents in patients with cancer ranges from 79.6-91.2%, and a free fraction of approximately 0.11 was observed in pooled human plasma over a concentration range of 234-1169 ng/mL. The presence of cisplatin, fluorouracil, or doxorubicin does not affect vinorelbine binding. Following IV administration of radiolabeled vinorelbine, approximately 46% of the administered dose was recovered in the feces and 18% in the urine. In another study, approximately 11% of an administered IV dose of vinorelbine was excreted unchanged in the urine. The effects of food on the pharmacokinetics and safety profile of a soft-gel capsule formulation of vinorelbine (Navelbine Oral) were evaluated in fed and fasted patients with solid tumours or lymphomas. A group of 18 patients (12 planned) were entered into a multicenter phase I pharmacokinetic study following a crossover design with a 1-week wash-out period. Patients received the first dose of 80 mg/sq m oral vinorelbine either after fasting or after ingestion of a standard continental breakfast. The second dose of 80 mg/sq m was administered 1 week later in the alternate feeding condition to the first dose. Of the 18 patients, 13 were eligible for pharmacokinetic evaluation. The mean time to maximum concentration (T(max)) was shorter in fasted patients (1.63+/-0.98 hr in blood, 1.67+/-0.96 hr in plasma) than in fed patients (2.48+/-1.40 hr in blood, 2.56+/-1.65 hr in plasma) but these differences are not likely to modify the safety and/or efficacy of oral vinorelbine. Values for C(max) and AUC were similar in fed and fasted patients and no significant differences were observed. The safety profile of oral vinorelbine observed in this limited number of patients appears to be comparable to that usually reported for vinorelbine, the main toxicity being neutropenia. Only one episode of febrile neutropenia was reported. The main nonhematological toxicities encountered were gastrointestinal, consisting of nausea, vomiting, diarrhea and constipation. A tendency for a lower incidence of vomiting was suggested when oral vinorelbine was administered after a standard breakfast. Based on this study, the administration of oral vinorelbine to fasted patients is not mandatory since administration after a standard breakfast does not lead to differences in body exposure to the drug. ... For more Absorption, Distribution and Excretion (Complete) data for VINORELBINE (9 total), please visit the HSDB record page. Metabolism / Metabolites Vinorelbine undergoes substantial hepatic elimination in humans. Two metabolites of vinorelbine have been identified in human blood, plasma, and urine; vinorelbine N-oxide and deacetylvinorelbine. Deacetylvinorelbine has been demonstrated to be the primary metabolite of vinorelbine in humans, and has been shown to possess antitumor activity similar to vinorelbine,. Vinorelbine is metabolized into two other minor metabolites, 20'-hydroxyvinorelbine and vinorelbine 6'-oxide. Therapeutic doses of vinorelbine (30 mg/m2) yield very small, if any, quantifiable levels of either metabolite in blood or urine. The metabolism of vinorelbine is mediated by hepatic cytochrome P450 isoenzymes in the CYP3A subfamily,. As the liver provides the main route for metabolism of the drug, patients with hepatic impairment may demonstrate increased toxicity with standard dosing, however, there are no available data on this. Likewise, the contribution of cytochrome P450 enzyme action to vinorelbine metabolism has potential implications in patients receiving other drugs metabolized by this route. Vinorelbine is extensively metabolized in the liver. The metabolism of vinca alkaloids (eg, vinblastine, vincristine) is mediated by the cytochrome P-450 (CYP) isoenzymes in the CYP3A subfamily. Two metabolites of vinorelbine, vinorelbine N-oxide and deacetylvinorelbine, have been identified in human blood, plasma, and urine. Deacetylvinorelbine, the primary metabolite of vinorelbine in humans, has been shown to possess antitumor activity similar to the parent drug. However, therapeutic doses of vinorelbine result in very small, if any, quantifiable concentrations of either metabolite in blood or urine. ... Little is known about the biotransformation of vinorelbine. Desacetylvinorelbine is considered to be a minor metabolite and is only found in urine fractions, representing 0.25% of the injected dose. ... ... Deacetylation yielding deacetylnavelbine (DNVB) is the primary metabolic route for vinorelbine (navelbine, NVB). This cytotoxic metabolite accounts for a substantial part of the overall disposition of drug. Only 58% of the administered dose is excreted in the urine (17%) and feces (41%) as NVB or DNVB. No other metabolites have been detected. Vinorelbine produced a dominant metabolite (M1) after incubation with rat liver microsomes. Several major metabolites other than M1 were identified by HPLC in bile and feces of rat after intravenous administration. The structures of the major metabolites were identified as 15,16-epoxyvinorelbine (M1), 11'-hydroxyvinorelbine (M2), 19'-hydroxyvinorelbine (M3a), 15,16-epoxy-10'-hydroxyvinorelbine (M3b) and 10'-hydroxyvinorelbine (M4) by comparison of HPLC retention times and by extensive analyses of two-dimensional NMR and hybrid MS/MS spectra. Biological Half-Life The terminal phase half-life averaged 27.7 to 43.6 hours; the mean plasma clearances ranged from 0.97 to 1.26 L/hr/kg. The 3 phases of plasma decline of vinorelbine concentrations represent an initial rapid decline in plasma concentrations caused by distribution of the drug to peripheral compartments followed by metabolism and excretion of the drug and a prolonged terminal phase because of relatively slow efflux of drug from peripheral compartments. A mean terminal elimination half-life of 27.7-43.6 hours and a mean plasma clearance of 0.97-1.26 L/hour per kg have been reported for vinorelbine. ... There is a prolonged terminal phase due to relatively slow efflux of the drug from peripheral compartments, which results in a long terminal phase half-life, with average values ranging from 27.7 to 43.6 hours. ... ... In children, vinorelbine seems to display a shorter t1/2 (14.7 hours) than that found in adults. In addition, the systemic clearance is highly variable [from 12 to 93.96 L/hr/sq m (200 to 1566 mL/min/sq m)]. |
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| Toxicity/Toxicokinetics |
Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation Most sources consider breastfeeding to be contraindicated during maternal antineoplastic drug therapy. It is probably impractical to resume breastfeeding after vinorelbine therapy because of the drug's long half-life. Chemotherapy may adversely affect the normal microbiome and chemical makeup of breastmilk. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk A woman diagnosed with Hodgkin's lymphoma during the second trimester of pregnancy received 3 rounds of chemotherapy during the third trimester of pregnancy and resumed chemotherapy 4 weeks postpartum. Milk samples were collected 15 to 30 minutes before and after chemotherapy for 16 weeks after restarting. The regimen consisted of doxorubicin 40 mg, bleomycin 16 units, vinblastine 9.6 mg and dacarbazine 600 mg, all given over a 2-hour period every 2 weeks. The microbial population and metabolic profile of her milk were compared to those of 8 healthy women who were not receiving chemotherapy. The breastmilk microbial population in the patient was markedly different from that of the healthy women, with increases in Acinetobacter sp., Xanthomonadacae and Stenotrophomonas sp. and decreases in Bifidobacterium sp. and Eubacterium sp. Marked differences were also found among numerous chemical components in the breastmilk of the treated woman, most notably DHA and inositol were decreased. Protein Binding 80-90% Interactions Concomitant administration of vinorelbine and paclitaxel may be associated with an increased risk of neuropathy. Caution and careful monitoring are advised during concomitant use of a vinca alkaloid and aprepitant, an antiemetic agent, which may inhibit or induce CYP3A4. Because vestibular deficits and varying degrees of permanent or temporary hearing impairment associated with damage of the eighth cranial nerve have been reported in patients receiving vinca alkaloids, vinorelbine should be used concomitantly with other potentially ototoxic drugs, such as platinum-containing antineoplastic agents, with extreme caution. A 41-year-old woman had undergone a left mastectomy breast cancer three years prior to presentation. Six months /ago/ she had recurrence, this time in the right breast and skin. Despite first-and second-line chemotherapy, the mass showed progression of the disease. Thereafter, a weekly treatment of vinorelbine and trastuzumab was started, but one month later, she developed a slight fever and dry cough. A chest CT scan revealed an infiltration shadow showing non-specific interstitial pattern in the right lung. A bronchoscopic examination showed lymphocyte dominance in bronchial lavage fluid, and lymphocyte infiltration into the interstium with fibrosis in the tissue specimens was found by transbronchial lung biopsy. After discontinuing the above vinorelbine therapy, the patient's condition improved. /Investigators/ therefore diagnosed this as a case of vinorelbine-and trastuzumab-induced interstitial pneumonia. |
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| References | Semin Oncol.1989 Apr;16(2 Suppl 4):9-14;Eur J Cancer.1999 Mar;35(3):512-20. | ||
| Additional Infomation |
Therapeutic Uses Antineoplastic Agents, Phytogenic Vinorelbine is indicated as a single agent or in combination with cisplatin for the first-line treatment of ambulatory patients with unresectable, advanced nonsmall cell lung cancer (NSCLC). In patients with Stage IV NSCLC, Vinorelbine is indicated as a single agent or in combination with cisplatin. In Stage III NSCLC, Vinorelbine is indicated in combination with cisplatin. /Included in US product label/ Combination therapy with vinorelbine and trastuzumab is being investigated as an active regimen for the treatment of HER2-overexpressing metastatic breast cancer. /Not included in US product label/ Vinorelbine is used as monotherapy in the first-line or salvage (e.g., second-line or subsequent) treatment of metastatic breast cancer. /Not included in US product label/ For more Therapeutic Uses (Complete) data for VINORELBINE (6 total), please visit the HSDB record page. Drug Warnings /BOXED WARNING/ WARNING: Vinorelbine should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. This product is for intravenous (IV) use only. Intrathecal administration of other vinca alkaloids has resulted in death. Syringes containing this product should be labeled "WARNING - FOR IV USE ONLY. FATAL if given intrathecally." Severe granulocytopenia resulting in increased susceptibility to infection may occur. Granulocyte counts should be = 1,000 cells/cu mm prior to the administration of vinorelbine. The dosage should be adjusted according to complete blood counts with differentials obtained on the day of treatment. Caution - It is extremely important that the intravenous needle or catheter be properly positioned before vinorelbine is injected. Administration of vinorelbine may result in extravasation causing local tissue necrosis and/or thrombophlebitis The major and dose-limiting adverse effect of vinorelbine is myelosuppression, manifested principally by granulocytopenia and leukopenia. The incidence of myelosuppression does not appear to be influenced by age or prior exposure to chemotherapy. Granulocyte counts less than 2000 and 500/cu mm occurred in 90 and 36% of patients, respectively. Leukopenia (less than 4000/cu mm) occurred in 92% of patients, and was severe (less than 1000 cells/cu mm) in 15% of patients. Leukopenia occurred at a similar rate in patients receiving vinorelbine and cisplatin in randomized trials (88 or 94%), but the rate of grade 3 or 4 leukopenia was higher (about 60%). Hospitalization for granulocytopenic complications (e.g., fever, sepsis, infection, pneumonia) occurred in 9% of patients. Hospitalization for documented sepsis was reported in about 4% of patients receiving vinorelbine either alone or with cisplatin. Septic death occurred in approximately 1% of patients. The manufacturer states that, although the pharmacokinetics of vinorelbine are not influenced by the concurrent administration of cisplatin, the incidence of granulocytopenia is higher when vinorelbine is used in combination with cisplatin than when it is used as a single agent. In a clinical trial in which patients were randomized to receive single-agent vinorelbine or vinorelbine plus cisplatin, grade 3 or 4 granulocytopenia occurred more frequently with the combination (79%) than with single-agent vinorelbine (53%). In another randomized trial, grade 3 or 4 granulocytopenia occurred more frequently in those receiving vinorelbine and cisplatin (82%) than in those receiving cisplatin alone (5%); fever and/or sepsis related to granulocytopenia occurred in 11% of patients receiving combination therapy compared with 0% of patients receiving cisplatin alone, and 4 patients receiving vinorelbine and cisplatin died of granulocytopenia-related sepsis. Death from febrile neutropenia occurred in 3 patients receiving vinorelbine and cisplatin. Infection (unspecified type) was reported in 11% of patients receiving vinorelbine and cisplatin compared with less than 1% of those receiving cisplatin alone, and severe infection occurred in 6% of patients receiving combination therapy. Respiratory infection was reported in patients receiving vinorelbine and cisplatin (10%) or cisplatin alone (3%). For more Drug Warnings (Complete) data for VINORELBINE (40 total), please visit the HSDB record page. Pharmacodynamics Vinorelbine is a semi-synthetic vinca-alkaloid with a wide spectrum of anti-tumor activity. The vinca-alkaloids are considered spindle poisons. They work by interfering with the polymerization of tubulin, a protein responsible for building the microtubule system which appears during cell division in proliferating cancer cells. |
Solubility Data
| Solubility (In Vitro) | May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples |
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples. Injection Formulations (e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] *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. Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline) Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline) Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline) Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil) Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Oral Formulations Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). Oral Formulation 3: Dissolved in PEG400 Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose Oral Formulation 6: Mixing with food powders Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.2838 mL | 6.4191 mL | 12.8381 mL | |
| 5 mM | 0.2568 mL | 1.2838 mL | 2.5676 mL | |
| 10 mM | 0.1284 mL | 0.6419 mL | 1.2838 mL |