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).

Absorption, Distribution and Excretion
The major route of excretion may be through the biliary system.
Vinblastine sulfate is unpredictably absorbed from the GI tract. Following iv administration, the drug is rapidly cleared from the blood and distributed into body tissues. Vinblastine crosses the blood brain barrier poorly and does not appear in the CSF in therapeutic concentrations.
The volume of the central compartment is 70% of body weight, probably reflecting very rapid tissue binding to formed elements of the blood. Extensive reversible tissue binding occurs. Low body stores are present at 48 and 72 hours after injection.
Following injection of tritiated vinblastine in the human cancer patient, 10% of the radioactivity was found in the feces and 14% in the urine; the remaining activity was not accounted for. Similar studies in dogs demonstrated that, over 9 days, 30% to 36% of radioactivity was found in the bile and 12% to 17% in the urine. A similar study in the rat demonstrated that the highest concentrations of radioactivity were found in the lung, liver, spleen, and kidney 2 hours after injection.
It is not known whether this drug is excreted in human milk.
For more Absorption, Distribution and Excretion (Complete) data for VINBLASTINE (9 total), please visit the HSDB record page.

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Metabolism / Metabolites
Hepatic. Metabolism of vinblastine has been shown to be mediated by hepatic cytochrome P450 3A isoenzymes.
Vinblastine is reported to be extensively metabolized, primarily in the liver, to desacetylvinblastine, which is more active than the parent compound on a weight basis.
Since the major route of excretion may be through the biliary system, toxicity from this drug may be increased when there is hepatic excretory insufficiency. The metabolism of vinca alkaloids has been shown to be mediated by hepatic cytochrome P450 isoenzymes in the CYP 3A subfamily. This metabolic pathway may be impaired in patients with hepatic dysfunction or who are taking concomitant potent inhibitors of these isoenzymes such as erythromycin.

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Biological Half-Life
Triphasic: 35 min, 53 min, and 19 hours
Pharmacokinetic studies in patients with cancer have shown a triphasic serum decay pattern following rapid intravenous injection. The initial, middle, and terminal half-lives are 3.7 minutes, 1.6 hours, and 24.8 hours, respectively.
The elimination of VLB from the plasma of patients who received it by 5-day iv infusion at 1 to 2 mg/sq m daily was biphasic. In four patients who achieved partial remission, the average plasma half-life of VLB during the terminal phase was 29.4 +/- 14.6 days ... However, in three patients whose disease merely stabilized, the plasma half-life was 6.4 +/- 1.6 days ... In contrast, in five patients with refractory disease, this parameters was 2.3 +/- 0.3 days...
The pharmacokinetics of vinblastine in humans was examined using a radioimmunoassay specific for both the Vinca alkaloids and aromatic ring [3H]vinblastine. The data were consistent with a three-compartment open model system with the following values, alpha phase: t1/2=3.90+/-1.46 min; Vc=16.8+/-7.1 liters. beta phase:t1/2=53.0+/-13.0 min; Vbeta=79.0+/-52.0 liters; gamma phase:t1/2=1173.0+/-65.0 min; Vgamma=1656.0+/-717.0 liters. ...

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 vinblastine therapy because of the drug's long half-life. Chemotherapy may adversely affect the normal microbiome and chemical makeup of breastmilk. Women who receive chemotherapy during pregnancy are more likely to have difficulty nursing their infant.
◉ 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.
A telephone follow-up study was conducted on 74 women who received cancer chemotherapy at one center during the second or third trimester of pregnancy to determine if they were successful at breastfeeding postpartum. Only 34% of the women were able to exclusively breastfeed their infants, and 66% of the women reported experiencing breastfeeding difficulties. This was in comparison to a 91% breastfeeding success rate in 22 other mothers diagnosed during pregnancy, but not treated with chemotherapy. Other statistically significant correlations included: 1. mothers with breastfeeding difficulties had an average of 5.5 cycles of chemotherapy compared with 3.8 cycles among mothers who had no difficulties; and 2. mothers with breastfeeding difficulties received their first cycle of chemotherapy on average 3.4 weeks earlier in pregnancy. Of the 6 women who received a vincristine-containing regimen, 5 had breastfeeding difficulties.

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Protein Binding
98-99%

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Interactions
Caution should be exercised in patients concurrently taking drugs known to inhibit drug metabolism by hepatic cytochrome P450 isoenzymes in the CYP 3A subfamily, or in patients with hepatic dysfunction. Concurrent administration of vinblastine sulfate with an inhibitor of this metabolic pathway may cause an earlier onset and/or an increased severity of side effects.
The simultaneous oral or intravenous administration of phenytoin and antineoplastic chemotherapy combinations that included vinblastine sulfate has been reported to have reduced blood levels of the anticonvulsant and to have increased seizure activity.
Potential synergistic interactions between vinblastine and recombinant interferon-beta were assessed using median effect analysis. Calculation of the combination index demonstrated values less than 1 (indicating synergy) over a wide range of drug induced growth inhibition for each of four different renal carcinoma cell lines. The degree of synergy observed could not be predicted from the morphology, doubling time, or relative sensitivity of the renal carcinoma cell lines to vinblastine and recombinant interferon-beta. The optimal ratio of vinblastine to recombinant interferon-beta in the combination appeared to be close to the ratio of the concn of each agent which yielded a 50% inhibition of growth. Although simultaneous presence of vinblastine and recombinant interferon-beta in the culture medium was not required to demonstrate a synergistic effect, the minimum exposure time for recombinant interferon-beta was determined to be 7 days. The uptake but not the egress of tritiated vinblastine into renal carcinoma cell line cells was enhanced after growth for 4 days in 2.25 ng/mL of recombinant interferon-beta. Median effect analysis can be shown to be independent of the mechanism of action of vinblastine and recombinant interferon-beta and gives an indication of potential synergistic interactions over a wide range of drug effects. This method may prove useful in the selection of combinations of IFNs and antitumor drugs for clinical study.
A HIV infected patient was treated for stage IVB Hodgkin's lymphoma by ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) chemotherapy and lopinavir-ritonavir based antiretroviral therapy inducing profound life-threatening neutropenia. Vinblastine and lopinavir-ritonavir interaction was managed with lopinavir-ritonavir interruption around chemotherapy administration, with complete remission and immunovirological success after six cycles.
For more Interactions (Complete) data for VINBLASTINE (6 total), please visit the HSDB record page.

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

Antitumor alkaloid isolated from Vinca rosea. (Merck, 11th ed.)
Vinblastine is a Vinca Alkaloid.
Vinblastine has been reported in Catharanthus trichophyllus, Tabernaemontana laeta, and other organisms with data available.
Vinblastine is a natural alkaloid isolated from the plant Vinca rosea Linn. Vinblastine binds to tubulin and inhibits microtubule formation, resulting in disruption of mitotic spindle assembly and arrest of tumor cells in the M phase of the cell cycle. This agent may also interfere with amino acid, cyclic AMP, and glutathione metabolism; calmodulin-dependent Ca++ -transport ATPase activity; cellular respiration; and nucleic acid and lipid biosynthesis. (NCI04)
Antitumor alkaloid isolated from Vinca rosea. (Merck, 11th ed.)
See also: Vinblastine Sulfate (has salt form).

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Drug Indication
For treatment of breast cancer, testicular cancer, lymphomas, neuroblastoma, Hodgkin's and non-Hodgkin's lymphomas, mycosis fungoides, histiocytosis, and Kaposi's sarcoma.

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Mechanism of Action
The antitumor activity of vinblastine is thought to be due primarily to inhibition of mitosis at metaphase through its interaction with tubulin. Vinblastine binds to the microtubular proteins of the mitotic spindle, leading to crystallization of the microtubule and mitotic arrest or cell death.
Although the mechanism of action has not been definitely established, vinblastine appears to bind to or crystallize critical microtubular proteins of the mitotic spindle, thus preventing their proper polymerization and causing metaphase arrest. In high concentrations, vinblastine also exerts complex effects on nucleic acid and protein synthesis. Vinblastine reportedly also interferes with amino acid metabolism by blocking cellular utilization of glutamic acid and thus inhibits purine synthesis, the citric acid cycle, and the formation of urea. Vinblastine exerts some immunosuppressive activity.
Experimental data indicate that the action of vinblastine sulfate is different from that of other recognized antineoplastic agents. Tissue-culture studies suggest an interference with metabolic pathways of amino acids leading from glutamic acid to the citric acid cycle and to urea. In vivo experiments tend to confirm the in vitro results. A number of in vitro and in vivo studies have demonstrated that vinblastine sulfate produces a stathmokinetic effect and various atypical mitotic figures.
... Studies indicate that vinblastine sulfate has an effect on cell-energy production required for mitosis and interferes with nucleic acid synthesis. The mechanism of action of vinblastine sulfate has been related to the inhibition of microtubule formation in the mitotic spindle, resulting in an arrest of dividing cells at the metaphase stage.
Reversal of the antitumor effect of vinblastine sulfate by glutamic acid or tryptophan has been observed. In addition, glutamic acid and aspartic acid have protected mice from lethal doses of vinblastine sulfate. Aspartic acid was relatively ineffective in reversing the antitumor effect.

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Therapeutic Uses
Antineoplastic Agents, Phytogenic
Vinblastine sulfate is indicated in the palliative treatment of the following: Frequently Responsive Malignancies: Generalized Hodgkin's disease (Stages III and IV, Ann Arbor modification of Rye staging system), Lymphocytic lymphoma (nodular and diffuse, poorly and well differentiated), histiocytic lymphoma, mycosis fungoides (advanced stages), advanced carcinoma of the testis, Kaposi's sarcoma, Letterer-Siwe disease (histiocytosis X). Less Frequently Responsive Malignancies: Choriocarcinoma resistant to other chemotherapeutic agents, carcinoma of the breast, unresponsive to appropriate endocrine surgery and hormonal therapy. Current principles of chemotherapy for many types of cancer include the concurrent administration of several antineoplastic agents. For enhanced therapeutic effect without additive toxicity, agents with different dose-limiting clinical toxicities and different mechanisms of action are generally selected. Therefore, although vinblastine sulfate is effective as a single agent in the aforementioned indications, it is usually administered in combination with other antineoplastic drugs. /Included in US product label/
Vinblastine sulfate has been shown to be one of the most effective single agents for the treatment of Hodgkin's disease. Advanced Hodgkin's disease has also been successfully treated with several multiple-drug regimens that included vinblastine sulfate. /Included in US product label/
Advanced testicular germinal-cell cancers (embryonal carcinoma, teratocarcinoma, and choriocarcinoma) are sensitive to vinblastine sulfate alone, but better clinical results are achieved when vinblastine sulfate is administered concomitantly with other antineoplastic agents. /Included in US product label/
For more Therapeutic Uses (Complete) data for VINBLASTINE (11 total), please visit the HSDB record page.

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Drug Warnings
This preparation is for intravenous use only. It should be administered by individuals experienced in the administration of vinblastine sulfate injection. The intrathecal administration of vinblastine sulfate injection usually results in death. Syringes containing this product should be labeled, using the auxiliary sticker provided, to state "FATAL IF GIVEN INTRATHECALLY. FOR INTRAVENOUS USE ONLY."
Vinblastine sulfate is contraindicated in patients who have significant granulocytopenia unless this is a result of the disease being treated.
The major adverse effect of vinblastine is hematologic toxicity which occurs much more frequently than with vincristine therapy. Leukopenia (granulocytopenia) occurs most commonly and is usually the dose limiting factor in vinblastine therapy; however, numerous patients have achieved a sustained remission without leukopenia. Leukopenia may not be a problem with small doses used for maintenance therapy; however, the possibility of a cumulative effect should be considered. The nadir in the leukocyte count usually occurs 4-10 days after administration of vinblastine. Recovery occurs rapidly, usually within another 7-14 days; however, following administration of high doses of vinblastine, recovery may take 21 days or more. ... Although thrombocytopenia is usually slight and transient, substantial platelet count depression may occur, particularly in patients who have received prior radiation therapy or chemotherapy. In patients whose bone marrow has been infiltrated with malignant cells, vinblastine may produce an abrupt fall in the leukocyte and thrombocyte counts. ... Anemia also may occur in patients receiving vinblastine.
Acute shortness of breath and bronchospasm, which can be severe or life threatening, have occurred following administration of vinca alkaloids (e.g., vinblastine), being reported most frequently when mitomycin was administered concomitantly. Such reactions may occur a few minutes to several hours after administration of a vinca alkaloid or up to 2 wk after a dose of mitomycin. Progressive dyspnea ... can occur in patients receiving vinblastine; the drug should not be readministered to these patients.
For more Drug Warnings (Complete) data for VINBLASTINE (21 total), please visit the HSDB record page.

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Pharmacodynamics
Vinblastine is a vinca alkaloid antineoplastic agent. The vinca alkaloids are structurally similar compounds comprised of 2 multiringed units: vindoline and catharanthine. The vinca alkaloids have become clinically useful since the discovery of their antitumour properties in 1959. Initially, extracts of the periwinkle plant (Catharanthus roseus) were investigated because of putative hypoglycemic properties, but were noted to cause marrow suppression in rats and antileukemic effects in vitro. Vinblastine has some immunosuppressant effect. The vinca alkaloids are considered to be cell cycle phase-specific.

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.)