In vivo, Vinorelbine also shows antitumour activity against a series of subcutaneously-implanted human tumour xenografts.

Absorption, Distribution and Excretion
Vinorelbine is rapidly absorbed, reaching peak serum concentrations within 2 hours. It binds strongly to platelets and lymphocytes, as well as to α1-acid glycoprotein, albumin, and lipoprotein. Vinorelbine is primarily excreted through the liver in the human body. After intravenous administration, a large amount of the drug is excreted in the feces. Less than 20% of the unchanged drug is excreted in the urine, and 30% to 60% is excreted in the feces. After intravenous injection of radioactive vinorelbine, approximately 18% and 46% of the administered radioactive material are excreted in the urine and feces, respectively. It has a large volume of distribution, indicating its widespread extravascular distribution. One study showed a steady-state volume of distribution of 25.4 to 40.1 L/kg. Vinorelbine is widely distributed, primarily in excretory organs such as the liver and kidneys, with extremely low concentrations in the heart and brain. Vinorelbine exhibits high plasma clearance, approaching human hepatic blood flow, and a large volume of distribution, indicating extensive extravascular distribution. Compared to vincristine or vinblastine, in four clinical trials, patients treated with 30 mg/m² vinorelbine showed clearance ranging from 0.29 to 1.26 L/kg. The initial rapid decrease in plasma vinorelbine concentration after intravenous injection indicates that the drug is being distributed to peripheral tissues. Steady-state volume of distribution of 25.4–40.1 L/kg has been reported 15–20 minutes after intravenous injection of 30 mg/m² vinorelbine. Vinorelbine binds well to human platelets and lymphocytes. In cancer patients, the drug binds to plasma components at rates of 79.6% to 91.2%, and a free fraction of approximately 0.11 was observed in mixed human plasma at concentrations ranging from 234 to 1169 ng/mL. The presence of cisplatin, fluorouracil, or doxorubicin does not affect the binding of vinorelbine. Following intravenous administration of radiolabeled vinorelbine, approximately 46% of the administered dose is recovered in feces and 18% in urine. In another study, approximately 11% of the intravenously administered vinorelbine dose was excreted unchanged in the urine. The effects of food on the pharmacokinetics and safety of vinorelbine soft capsules (Navelbine Oral) were evaluated in patients with solid tumors or lymphoma who were eating or fasting. A multicenter phase I pharmacokinetic study with a crossover design and a 1-week washout period enrolled 18 patients (planned for 12). Patients received an initial oral dose of 80 mg/m² of vinorelbine after fasting or after a standard continental breakfast. One week later, a second dose of 80 mg/m² was administered under different eating conditions than the initial dose. Of the 18 patients, 13 met the criteria for pharmacokinetic evaluation. The time to peak concentration (Tmax) was shorter in fasting patients than in patients who had eaten (2.48 ± 1.40 hours for plasma concentration and 2.56 ± 1.65 hours for total plasma concentration), but these differences are unlikely to affect the safety and/or efficacy of oral vinorelbine. Cmax and AUC values were similar in fasting and eating patients, with no significant differences observed. In the limited sample of this study, the safety profile of oral vinorelbine was comparable to that reported for vinorelbine, with the main toxicity being neutropenia. Only one case of febrile neutropenia was reported. The main non-hematologic toxicities were gastrointestinal reactions, including nausea, vomiting, diarrhea, and constipation. The study suggests a trend toward a lower incidence of vomiting when oral vinorelbine is taken after a standard breakfast. Based on this study, since taking it after a standard breakfast does not result in a difference in drug exposure, there is no need to mandate fasting for oral vinorelbine. ...
For more complete data on the absorption, distribution, and excretion of vinorelbine (9 types), please visit the HSDB record page.

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Metabolism/Metabolites
Vinorelbine is primarily metabolized and eliminated by the liver in the human body. Two vinorelbine metabolites have been identified in human blood, plasma, and urine: vinorelbine N-oxide and deacetylated vinorelbine. Deacetylated vinorelbine has been shown to be the major metabolite of vinorelbine in the human body and has similar antitumor activity to vinorelbine. Vinorelbine is also metabolized into two other minor metabolites: 20'-hydroxyvinorelbine and vinorelbine 6'-oxide. At therapeutic doses of vinorelbine (30 mg/m2), almost no quantifiable metabolites are detected in blood or urine. The metabolism of vinorelbine is primarily mediated by the hepatic cytochrome P450 isoenzyme CYP3A subfamily. Because the liver is the primary metabolic pathway for this drug, patients with impaired liver function may experience increased toxicity after taking standard doses, although no relevant data are currently available. Similarly, the role of cytochrome P450 enzymes in vinorelbine metabolism may also have potential effects on patients taking other drugs metabolized via this pathway. Vinorelbine is extensively metabolized in the liver. The metabolism of vinca alkaloids (e.g., vincristine, vinblastine) is also mediated by the cytochrome P450 (CYP) isoenzyme CYP3A subfamily. Two metabolites of vinorelbine, namely vinorelbine N-oxide and deacetylated vinorelbine, have been identified in human blood, plasma, and urine. Deacetylated vinorelbine is the major metabolite of vinorelbine in humans and has been shown to have antitumor activity similar to the parent drug. However, these two metabolites are almost undetectable in blood or urine at therapeutic doses of vinorelbine. …Little is known about the biotransformation of vinorelbine. Deacetylated vinorelbine is considered a minor metabolite, present only in urine, accounting for 0.25% of the injected dose. …
…Deacetylation to deacetylated vinorelbine (DNVB) is the major metabolic pathway of vinorelbine (NVB). This cytotoxic metabolite accounts for a large portion of the overall drug distribution. Only 58% of the administered dose is excreted in urine (17%) and feces (41%) as NVB or DNVB. No other metabolites were detected. Vinorelbine produces a major metabolite (M1) upon incubation with rat liver microsomes. Several major metabolites other than M1 were identified in rat bile and feces by high-performance liquid chromatography (HPLC) after intravenous administration. By comparing retention times in high-performance liquid chromatography (HPLC) and extensive analysis using two-dimensional nuclear magnetic resonance (NMR) and mixed tandem mass spectrometry (MS/MS), 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). The average biological half-life was 27.7 to 43.6 hours; the average plasma clearance ranged from 0.97 to 1.26 L/hr/kg. The decline in vinorelbine plasma concentration occurred in three phases: an initial phase, characterized by a rapid decrease in plasma concentration due to drug distribution to peripheral tissues; subsequent drug metabolism and excretion; and a final phase, where the relatively slow rate of drug elimination from peripheral tissues led to a prolonged terminal concentration decline. The mean terminal elimination half-life of vinorelbine is reported to be 27.7 to 43.6 hours, with a mean plasma clearance of 0.97 to 1.26 L/hr/kg. ...Due to the relatively slow rate of drug elimination from peripheral tissues, the terminal concentration decline is prolonged, with a mean range of 27.7 to 43.6 hours. ... ...In children, the half-life of vinorelbine (14.7 hours) appears to be shorter than in adults. Furthermore, systemic clearance varies considerably [from 12 to 93.96 L/hr/sq m (200 to 1566 mL/min/sq m)].

Effects During Pregnancy and Lactation
◉ Overview of Lactational Use
Most data suggest that breastfeeding is not advisable during mothers receiving anti-tumor drug treatment. Due to the long half-life of vinorelbine, resuming breastfeeding after completing vinorelbine treatment may be impractical. Chemotherapy may adversely affect the normal microbiota and chemical composition of breast milk. ◉ Effects on Breastfed Infants
No relevant published information was found as of the revision date. ◉ Effects on Lactation and Breast Milk
A woman diagnosed with Hodgkin's lymphoma in mid-pregnancy received three cycles of chemotherapy in late pregnancy and resumed chemotherapy four weeks postpartum. Breast milk samples were collected 15 to 30 minutes before and after chemotherapy within 16 weeks of restarting chemotherapy. The regimen consisted of doxorubicin 40 mg, bleomycin 16 units, vinblastine 9.6 mg, and dacarbazine 600 mg, administered intravenously every two weeks over two hours. Researchers compared the microbial community and metabolome of the patient's breast milk with those of eight healthy women who had not received chemotherapy. The results showed significant differences in the microbial community between the patient's and healthy women's milk, with increased abundance of Acinetobacter, Xanthomonas, and Stenotrophomonas maltophilia, while decreasing abundance of Bifidobacterium and Eubacterium. Several chemical components in the breast milk of the treated women also differed significantly, most notably with decreased DHA and inositol levels.
Protein binding rate
80-90%
Drug interactions
Vinorelbine combined with paclitaxel may increase the risk of neuropathy.
Caution and close monitoring are recommended when using vinca alkaloids and aprepitant (an antiemetic that may inhibit or induce CYP3A4).
Because patients treated with vinorelbine alkaloids have reported vestibular dysfunction and varying degrees of permanent or temporary hearing loss associated with eighth cranial nerve injury, vinorelbine should be used with extreme caution when combined with other potentially ototoxic drugs (such as platinum-based antineoplastic agents).
A 41-year-old woman who had undergone left-side surgery had undergone radical mastectomy for breast cancer three years prior. Six months ago, the tumor recurred, this time metastasizing to the right breast and skin. Despite first- and second-line chemotherapy, the tumor continued to progress. Subsequently, the patient began weekly treatment with vinorelbine in combination with trastuzumab. One month later, the patient developed mild fever and dry cough. Chest CT scan showed infiltrates in the right lung, presenting as nonspecific interstitial changes. Bronchoscopy revealed that the bronchoalveolar lavage fluid was predominantly lymphocyte-rich, and bronchopulmonary biopsy confirmed lymphocytic infiltration into the interstitium with fibrosis in the tissue specimen. After discontinuing the aforementioned vinorelbine treatment, the patient's condition improved. Therefore, the researchers diagnosed this case as interstitial pneumonia induced by vinorelbine combined with trastuzumab.

Semin Oncol.1989 Apr;16(2 Suppl 4):9-14;Eur J Cancer.1999 Mar;35(3):512-20.

Therapeutic Uses
Anti-tumor drug, plant-derived Vinorelbine can be used as monotherapy or in combination with cisplatin as first-line treatment for patients with unresectable advanced non-small cell lung cancer (NSCLC). For stage IV NSCLC patients, vinorelbine can be used as monotherapy or in combination with cisplatin. For stage III NSCLC patients, vinorelbine can be used in combination with cisplatin. /Included in the US product label/ Vinorelbine in combination with trastuzumab is being investigated as an effective treatment for HER2-overexpressing metastatic breast cancer. /Not included in the US product label/ Vinorelbine can be used as monotherapy for first-line or salvage (e.g., second-line or subsequent) treatment of metastatic breast cancer. /Not included in the US product label/ For more complete data on the therapeutic uses of vinorelbine (6 types), please visit the HSDB record page.

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Drug Warning
/Black Box Warning/ Warning: Vinorelbine should be used under the guidance of a physician experienced in the use of anticancer chemotherapy drugs. This product is for intravenous (IV) injection only. Intrathecal injection of other vinca alkaloids can be fatal. Syringes containing this product should be labeled "WARNING - For intravenous injection only. Intrathecal injection is fatal." Severe granulocytopenia may occur, leading to increased susceptibility to infection. A granulocyte count ≥1000/mm³ should be maintained before administration of vinorelbine. The dose should be adjusted based on the complete blood count and differential count obtained on the day of treatment. Note—It is crucial that the intravenous needle or catheter be correctly positioned before administering vinorelbine. Administration of vinorelbine may cause extravasation, resulting in local tissue necrosis and/or thrombophlebitis.
The main adverse reaction and dose-limiting adverse reaction of vinorelbine is myelosuppression, primarily manifested as granulocytopenia and leukopenia. The incidence of myelosuppression does not appear to be affected by age or previous chemotherapy history. 90% of patients had a granulocyte count below 2000/mm³, and 36% had a granulocyte count below 500/mm³. 92% of patients experienced leukopenia (below 4000/mm³), with 15% experiencing severe leukopenia (below 1000/mm³). In randomized trials, the incidence of leukopenia was similar in patients treated with vinorelbine and cisplatin (88% and 94%, respectively), but the incidence of grade 3 or 4 leukopenia was higher (approximately 60%). 9% of patients were hospitalized for complications of granulopenia (e.g., fever, sepsis, infection, pneumonia). Approximately 4% of patients receiving vinorelbine monotherapy or in combination with cisplatin reported hospitalization due to a confirmed diagnosis of sepsis. The mortality rate from sepsis was approximately 1%. The manufacturer notes that although the pharmacokinetics of vinorelbine are not affected by cisplatin combination therapy, the incidence of granulopenia is higher with vinorelbine in combination with cisplatin compared to vinorelbine monotherapy. In one clinical trial, patients were randomized to receive either vinorelbine monotherapy or vinorelbine in combination with cisplatin. Results showed that the combination therapy group (79%) had a higher incidence of grade 3 or 4 neutropenia than the vinorelbine monotherapy group (53%). In another randomized trial, patients receiving vinorelbine in combination with cisplatin (82%) had a higher incidence of grade 3 or 4 neutropenia than those receiving cisplatin monotherapy (5%). 11% of patients receiving combination therapy experienced neutropenia-related fever and/or sepsis, while none of these occurred in patients receiving cisplatin monotherapy. Four patients receiving vinorelbine in combination with cisplatin died from neutropenia-related sepsis. Three patients receiving vinorelbine in combination with cisplatin died from febrile neutropenia. 11% of patients receiving vinorelbine in combination with cisplatin reported infections (unspecified type), compared to less than 1% in patients receiving cisplatin alone; 6% of patients receiving combination therapy experienced serious infections. Respiratory tract infections were reported in 10% of patients receiving vinorelbine in combination with cisplatin, compared to 3% of patients receiving cisplatin alone. For more complete data on vinorelbine (40 total), please visit the HSDB records page.
Pharmacodynamics
Vinorelbine is a semi-synthetic vinca alkaloid with broad-spectrum antitumor activity. Vinca alkaloids are considered spindle toxins. They exert their effects by interfering with the polymerization of tubulin, a protein responsible for building the microtubule system and present during cell division in proliferating cancer cells.

C45H54N4O8

778.9323

778.394

71486-22-1

125317-39-7 (tartrate);105661-07-2 (tartrate 1:1);71486-22-1;

5311497

Typically exists as solid at room temperature

1.4±0.1 g/cm3

181-183

1.676

4.69

2

11

10

57

1690

8

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]

GBABOYUKABKIAF-IELIFDKJSA-N

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

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

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)

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

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.

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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).

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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)

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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).

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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

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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.

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 (Please use freshly prepared in vivo formulations for optimal results.)