vinblastine targets nicotinic acetylcholine receptor (nAChR) in adrenal chromaffin cells (IC50 for inhibiting nAChR-stimulated catecholamine release: 8.9 μM, 95% confidence limit 7.1–11.1 μM). [1]

The average terminal half-lives of Vinblastine is 14.3 h. When incubated in freshly isolated rat hepatocytes, VLB penetrates rapidly and intensely into the cells, probably through a passive diffusion mechanism followed by tight cellular binding. Vinblastine inhibits the angiogenic response induced by adrenomedullin and is also positive for mitotic slippage, causing micronuclei in mononucleate cells with cytokinesis block. vinblastine gives significant increase in micronucleated mononucleated cells at concentrations that produced approximately 50% cell death and cytostasis or less as calculated using RPD, RICC and RCC.

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Cell Assay: Six-well treatment plates are set up that contained 5 × 104 cells/mL (Chinese hamster ovary (CHO) cells) in each well, suspended in 3 mL culture medium, and these are treated with vinblastine for 3 h followed by 21 h growth.

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In cultured bovine adrenal chromaffin cells, vinblastine (IC50 8.9 μM) inhibited acetylcholine-stimulated catecholamine release in a concentration-dependent manner, with full reduction to basal levels at sufficient concentrations; it did not affect basal release nor release stimulated by depolarizing concentrations of potassium, indicating specificity for nAChR. [1]
In rat phrenic nerve-hemidiaphragm preparations, vinblastine (10–200 μM) failed to inhibit muscle response to phrenic nerve stimulation, but produced a graded increase in baseline muscle tension that was concentration-related (EC50 ~88 μM, 95% confidence limit 21–370 μM, estimated maximum developed resting tension 0.61 g by extrapolation). This elevation in baseline tension was reversible, unaffected by d-tubocurarine (1 μM) but dependent on extracellular calcium. [1]
In unstimulated rat diaphragm strips, vinblastine (20–200 μM) produced a dose-dependent contraction that was prevented in calcium-free Krebs solution and restored upon addition of calcium (2 mM). [1]

Vinblastine is a widely used anticancer drug with undesired side effects. A combination of VBL and RAP at very low doses against human HCC gets a satisfactory antiangiogenic effect in vivo. The clinically relevant dose of vinblastine inhibits palmitoylation of tubulin in vivo in CEM cells (effect on depalmitoylation of tubulin).

The study did not perform enzyme or receptor binding assays. [1]

Isolation and primary culture of bovine adrenal chromaffin cells: Adrenal glands were obtained, chromaffin cells dissociated, plated, and maintained at 37°C in humidified 5% CO2 environment. For secretion studies, cells were pretreated with vinblastine for 30 min in a physiologic salt solution containing 2 mM Ca2+ and 0.5% bovine serum albumin. Then cells were stimulated with 100 μM acetylcholine for 10 min in the continued presence of drug. Catecholamine release was monitored using a [3H]norepinephrine ([3H]NE) assay: cells were preloaded with [3H]NE, the amount of radioactivity released during stimulation was determined by liquid scintillation spectroscopy, and remaining radioactivity in cells was extracted with 8% trichloroacetic acid. Results expressed as percentage of net stimulated control response after subtracting basal (non-stimulated) fractional release. [1]
Rat phrenic nerve-hemidiaphragm preparation: Left phrenic nerve-hemidiaphragm muscles from adult rats were suspended in 35°C Krebs medium aerated with 95% O2 and 5% CO2. A 0.5 g resting tension was imposed, and isometric contractions recorded via force displacement transducer. Muscles were driven by repetitive (0.5 Hz) stimulation of the phrenic nerve (square wave pulses of 1 msec duration at two times threshold voltage, threshold 0.1–0.4 V). Drug concentrations expressed as molar bath concentrations. Vinblastine was added cumulatively (10–200 μM) and effects on contraction amplitude and baseline tension recorded. [1]
Rat diaphragm strips: Strips of diaphragm muscle (approx. 4×15 mm) were mounted in tissue bath under same conditions as phrenic nerve-hemidiaphragm preparation, but all extrinsic nerves were sectioned and no electrical excitation used. Cumulative doses of vinblastine (20–200 μM) were added, and changes in resting tension recorded. Calcium-free Krebs solution and calcium re-addition experiments were performed. [1]

Absorption, Distribution and Excretion
The primary route of excretion is likely the biliary system. Absorption of vinca sulfate in the gastrointestinal tract is unpredictable. Following intravenous administration, the drug is rapidly cleared from the blood and distributed throughout the body. Vinca sulfate has difficulty crossing the blood-brain barrier and cannot reach therapeutic concentrations in cerebrospinal fluid. The central septum has a volume of 70% of body weight, which may reflect rapid tissue binding of the drug to blood components. Extensive reversible tissue binding exists. Drug levels are low at 48 and 72 hours post-injection. In human cancer patients, after injection of tritium-labeled vinca sulfate, 10% of the radioactive material was found in feces, 14% in urine, and the fate of the remaining radioactive material is unknown. Similar studies in dogs showed that within 9 days, 30% to 36% of the radioactive material was found in bile, and 12% to 17% in urine. Similar studies in rats showed that the highest concentrations of radioactive material were found in the lungs, liver, spleen, and kidneys 2 hours post-injection. It is unclear whether this drug is excreted into human breast milk. For more complete data on the absorption, distribution, and excretion of vinblastines (9 in total), please visit the HSDB record page. Metabolism/Metabolites Hepatitis. The metabolism of vinblastines has been shown to be mediated by hepatic cytochrome P450 3A isoenzymes. Vinblastines have been reported to be extensively metabolized in the liver primarily to deacetylated vinblastine, which has a higher activity by weight than the parent compound. Since its primary excretion route is likely the biliary system, the toxicity of this drug may increase when hepatic excretion is impaired. The metabolism of vinblastines has been shown to be mediated by hepatic cytochrome P450 isoenzymes of the CYP 3A subfamily. The metabolic pathway may be impaired in patients with hepatic impairment or those taking potent isoenzyme inhibitors such as erythromycin.

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Biological Half-Life
Triphas: 35 min, 53 min, and 19 hours
Pharmacokinetic studies in cancer patients showed a triphasic decay pattern in serum drug concentrations following rapid intravenous injection. The initial, intermediate, and terminal half-lives were 3.7 min, 1.6 h, and 24.8 h, respectively.
After 5 days of intravenous infusion at doses of 1 to 2 mg/m² daily, the elimination of VLB from patients' plasma was biphasic. In four patients achieving partial remission, the mean plasma half-life of vinblastine at the terminal stage was 29.4 ± 14.6 days… However, in three patients with only stable disease, the plasma half-life was 6.4 ± 1.6 days… In contrast, in five patients with refractory disease, this parameter was 2.3 ± 0.3 days…
The pharmacokinetics of vinblastine in humans were investigated using radioimmunoassay targeting vinblastine alkaloids and aromatic ring [3H]vinblastine. The data are consistent with the three-compartment open model system, with the following values: α phase: t1/2 = 3.90 ± 1.46 minutes; Vc = 16.8 ± 7.1 liters. β phase: t1/2 = 53.0 ± 13.0 minutes; Vbeta = 79.0 ± 52.0 liters; γ phase: t1/2 = 1173.0 +/- 65.0 minutes; Vgamma = 1656.0 +/- 717.0 liters. ...

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Effects During Pregnancy and Lactation
◉ Overview of Lactational Use
Most data suggest that mothers should not breastfeed while receiving anti-tumor drug treatment. Due to the long half-life of vinblastine, resuming breastfeeding after vinblastine treatment may not be practical. Chemotherapy may adversely affect the normal microbiota and chemical composition of breast milk. Women receiving chemotherapy during pregnancy are more likely to experience breastfeeding difficulties. ◉ Effects on Breastfed Infants
As of the revision date, no relevant published information was found. ◉ 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 after resuming chemotherapy. The regimen consisted of doxorubicin 40 mg, bleomycin 16 units, vinblastine 9.6 mg, and dacarbazine 600 mg, administered every two weeks over two hours. Researchers compared the microbiome and metabolome of this patient's breast milk with those of eight healthy women who did not receive chemotherapy. The results showed a significant difference between the patient's and healthy women's breast milk microbiome, with increased numbers of Acinetobacter, Xanthomonas, and Stenotrophomonas maltophilia, and decreased numbers of Bifidobacterium and Eubacterium. Furthermore, several chemical components in the patient's breast milk also differed significantly, with significantly lower levels of DHA and inositol. A telephone follow-up study investigated 74 women who received chemotherapy for cancer in the second or third trimester at the same center to determine their postpartum breastfeeding success rate. Only 34% of the women were able to exclusively breastfeed their infants, and 66% reported difficulties during breastfeeding. In contrast, among the 22 mothers diagnosed during pregnancy but who did not receive chemotherapy, the breastfeeding success rate was as high as 91%. Other statistically significant correlations included: 1. Mothers with breastfeeding difficulties received an average of 5.5 cycles of chemotherapy, while mothers without breastfeeding difficulties received an average of 3.8 cycles; 2. Mothers with breastfeeding difficulties received their first chemotherapy on average 3.4 weeks earlier than mothers without breastfeeding difficulties. Of the 6 women treated with vincristine-containing regimens, 5 experienced breastfeeding difficulties. Protein binding rate: 98-99% Drug interactions: This product should be used with caution in patients taking medications known to inhibit the metabolism of CYP3A subfamily hepatic cytochrome P450 isoenzymes, or in patients with hepatic impairment. Concomitant use of vincristine sulfate with inhibitors of this metabolic pathway may lead to earlier onset and/or worsening of side effects. It has been reported that concomitant oral or intravenous administration of phenytoin sodium and antitumor chemotherapy drugs containing vincristine sulfate can reduce the blood concentration of anticonvulsants and increase seizure frequency.
Median effect-wise analysis was used to assess the potential synergistic effect between vinblastine and recombinant interferon-β. Combination indices were calculated for four different renal cell carcinoma lines, and the results showed that the combination indices were all less than 1 (indicating synergistic effect) within the range of drug-induced growth inhibition. The degree of observed synergistic effect could not be predicted based on the morphology, doubling time, or relative sensitivity of the renal cell carcinoma lines to vinblastine and recombinant interferon-β. The optimal ratio of vinblastine to recombinant interferon-β in the combination therapy appeared to be close to the ratio at which both drug concentrations achieved 50% growth inhibition. Although the co-presence of vinblastine and recombinant interferon-β in the culture medium was not a necessary condition for synergistic effect, the minimum exposure time to recombinant interferon-β was 7 days. After 4 days of culture in 2.25 ng/mL recombinant interferon-β, the renal cell carcinoma lines showed increased uptake of tritium-labeled vinblastine, but no increase in efflux. Median effect-wise analysis indicated that the mechanisms of action of vinblastine and recombinant interferon-β were unrelated and could indicate potential synergistic effects across a broad range of drug effects. This method may be helpful in selecting combinations of interferon and antitumor drugs for clinical research. A patient with HIV-infected disease developed severe, life-threatening granulocytopenia after receiving ABVD (doxacin, bleomycin, vincristine, dacarbazine) chemotherapy and lopinavir/ritonavir-based antiretroviral therapy for stage IVB Hodgkin lymphoma. By controlling the interaction between vincristine and lopinavir/ritonavir during chemotherapy, the patient achieved complete remission and immunovirological success after six cycles. More complete data on vincristine interactions (out of 6) can be found on the HSDB record page.

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Proc Soc Exp Biol Med.1993 Jul;203(3):372-6;Oncogene.2003 Sep 25;22(41):6458-61.

Antitumor alkaloids isolated from periwinkle. (Merck, 11th edition)
Vincine is a periwinkle alkaloid.
Vincine has been reported in Catharanthus trichophyllus, Tabernaemontana laeta, and other organisms with relevant data.
Vincine is a natural alkaloid isolated from periwinkle (Vinca rosea Linn.). Vincine binds to tubulin and inhibits microtubule formation, leading to disordered mitotic spindle assembly and arresting tumor cells in the M phase of the cell cycle. This drug may also interfere with the metabolism of amino acids, cyclic adenosine monophosphate (cAMP), and glutathione; calmodulin-dependent Ca++ transporter ATPase activity; cellular respiration; and the biosynthesis of nucleic acids and lipids. (NCI04)
Antitumor alkaloids isolated from periwinkle. (Merck, 11th edition)
See also: Vincine sulfate (salt form). Drug Indications Vincristine is used to treat breast cancer, testicular cancer, lymphoma, neuroblastoma, Hodgkin's lymphoma and non-Hodgkin's lymphoma, mycosis fungoides, histiocytosis, and Kaposi's sarcoma. Mechanism of Action The antitumor activity of vinblastine is believed to be primarily attributed to its interaction with tubulin, thereby inhibiting metaphase of mitosis. Vincristine binds to tubulin in the mitotic spindle, leading to microtubule crystallization, which in turn causes mitotic arrest or cell death. Although its mechanism of action is not fully elucidated, vinblastine appears to bind to or crystallize key tubulin in the mitotic spindle, preventing its normal polymerization and leading to metaphase arrest. High concentrations of vinblastine also have complex effects on nucleic acid and protein synthesis. Vinblastine has been reported to interfere with amino acid metabolism by blocking cellular utilization of glutamate, thereby inhibiting purine synthesis, the citric acid cycle, and urea production. Vincristine also possesses certain immunosuppressive activity. Experimental data indicate that the mechanism of action of vinblastine sulfate differs from other known antitumor drugs. Tissue culture studies show that vinblastine sulfate interferes with the amino acid metabolic pathway from glutamate to the citrate cycle and then to urea. In vivo results are largely consistent with in vitro results. Numerous in vitro and in vivo studies have shown that vinblastine sulfate inhibits cell division and leads to various atypical mitotic figures. Studies have shown that vinblastine sulfate affects the production of cellular energy required for mitosis and interferes with nucleic acid synthesis. The mechanism of action of vinblastine sulfate is related to the inhibition of microtubule formation in the mitotic spindle, leading to cell division arrest at metaphase. Glutamate or tryptophan can reverse the antitumor effect of vinblastine sulfate. Furthermore, glutamate and aspartic acid can protect mice from lethal doses of vinblastine sulfate. Aspartic acid is relatively less effective in reversing the antitumor effect.

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Therapeutic Uses
Antitumor drug, plant-derived
Vincristine sulfate is indicated for palliative treatment of the following diseases: Common and effective malignancies: Systemic Hodgkin lymphoma (stages III and IV, Ann Arbor modified Rye staging system), lymphocytic lymphoma (nodular and diffuse, poorly differentiated and well-differentiated), histiocytic lymphoma, mycosis fungoides (advanced stage), advanced testicular cancer, Kaposi's sarcoma, Letterer-Siwe disease (X-cell hyperplasia). Malignancies with poor efficacy: Choriocarcinoma resistant to other chemotherapy drugs, breast cancer unresponsive to appropriate endocrine surgery and hormone therapy. Currently, the principle of chemotherapy for many cancers includes the simultaneous use of multiple antitumor drugs. To enhance efficacy without increasing toxicity, drugs with different dose-limiting clinical toxicities and different mechanisms of action are usually selected. Therefore, although vincristine sulfate monotherapy is effective for the above indications, it is usually used in combination with other antitumor drugs. /US Product Label Content/
Vincristine sulfate has been proven to be one of the most effective monotherapy treatments for Hodgkin's lymphoma. Advanced Hodgkin's lymphoma has also been successfully treated with multidrug combination regimens containing vinblastine sulfate. /US Product Label Content/
Advanced testicular germ cell cancers (embryonic carcinoma, teratoma, and choriocarcinoma) are sensitive to vinblastine sulfate monotherapy, but better clinical efficacy can be achieved when used in combination with other antitumor drugs. /Included in US Product Label/
For more complete data on the therapeutic uses of vinblastine (11 types), please visit the HSDB record page.

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Drug Warning
This preparation is for intravenous injection only. Administration should be performed by a person experienced in administering vinblastine sulfate. Intrathecal administration of vinblastine sulfate is often fatal. Syringes containing this product should use the provided auxiliary label indicating \"Intrathecal injection fatal. For intravenous injection only.\"
Contraindicated in patients with severe granulocytopenia unless the granulocytopenia is caused by the disease being treated. The main adverse reaction of vinblastine is hematologic toxicity, which occurs far more frequently than with vincristine. Leukopenia (granulocytopenia) is the most common adverse reaction with vinblastine and is often a dose-limiting factor; however, many patients achieve sustained remission without leukopenia. Low doses of vinblastine used in maintenance therapy may not cause leukopenia; however, the possibility of a cumulative effect should be considered. The lowest white blood cell count usually occurs 4–10 days after vinblastine administration. Recovery is rapid, usually within 7–14 days; however, after high doses of vinblastine, recovery may take 21 days or longer. …While thrombocytopenia is usually mild and transient, a significant drop in platelet count can occur, especially in patients who have previously received radiotherapy or chemotherapy. In patients whose bone marrow is infiltrated by malignant cells, vinblastine may cause a sudden drop in white blood cell and platelet counts. Anemia may also occur in patients receiving vinblastine.
Acute dyspnea and bronchospasm have been reported after taking vinca alkaloids (such as vincristine), and these symptoms can be severe and even life-threatening, especially when taken concurrently with mitomycin. Such reactions can occur from minutes to hours after taking vinca alkaloids, or up to two weeks after taking mitomycin. Patients treated with vincristine may experience progressive dyspnea; these patients should not be given the drug again.
For more complete data on drug warnings for vincristine (21 in total), please visit the HSDB record page.

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Pharmacodynamics
Vinca alkaloids are antitumor drugs belonging to the class of vinca alkaloids. Vinca alkaloids are structurally similar compounds composed of two polycyclic units: vincristine and vinblastine. Since their antitumor properties were discovered in 1959, vinca alkaloids have been used clinically. Initially, extracts of vinca roseus (Catharanthus roseus) were studied for their potential hypoglycemic effects, but it was later discovered that they caused bone marrow suppression in rats and exhibited anti-leukemic activity in vitro. Vincristine has certain immunosuppressive effects. Vinca roseus alkaloids are believed to possess cell cycle specificity.

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vinblastine is a therapeutically useful antineoplastic drug that interferes with cell mitosis by promoting depolymerization of spindle fiber microtubules. Its anti-nAChR actions are selective for neuronal-type nAChR and do not extend to nAChR of mammalian skeletal muscle. The antimitotic and nAChR actions may be unrelated. vinblastine shares properties with noncompetitive inhibitors of the nAChR-gated ion channel (e.g., stabilizing a high affinity conformation of the nAChR complex). The contracture effect on diaphragm requires extracellular calcium and is reversible. [1]

C46H58N4O9

810.97

810.42

865-21-4

865-21-4;143-67-9 (sulfate);

13342

Solvated needles from methanol

1.4±0.1 g/cm3

211 - 216ºC

1.671

4.18

3

12

10

59

1700

9

C([C@@]12C=CCN3[C@@H]1[C@]1(C4C=C([C@]5(C[C@@H]6C[C@@](C[N@](C6)CCC6C7C=CC=CC=7NC5=6)(O)CC)C(=O)OC)C(=CC=4N(C)[C@H]1[C@@]([C@@H]2OC(=O)C)(O)C(=O)OC)OC)CC3)C

JXLYSJRDGCGARV-CFWMRBGOSA-N

InChI=1S/C46H58N4O9/c1-8-42(54)23-28-24-45(40(52)57-6,36-30(15-19-49(25-28)26-42)29-13-10-11-14-33(29)47-36)32-21-31-34(22-35(32)56-5)48(4)38-44(31)17-20-50-18-12-16-43(9-2,37(44)50)39(59-27(3)51)46(38,55)41(53)58-7/h10-14,16,21-22,28,37-39,47,54-55H,8-9,15,17-20,23-26H2,1-7H3/t28-,37-,38+,39+,42-,43+,44+,45-,46-/m0/s1

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)

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.)