VINBLASTINE

Toxicity

Oral, mouse: LD50 = 423 mg/kg; Oral, rat: LD50 = 305 mg/kg.

Description

An alkaloid derived from the periwinkle, Catharanthus roseus (formerly Vinca rosea) used as an antitumor drug in the treatment of Hodgkins lymphoma and other cancers. It binds to the microtubule subunit, tubulin, at a site distinct from that of colchicine and podophyllotoxin. This binding is reversible, temperature dependent and rapid, and results in large tubulin aggregates of highly ordered structure (vinblastine paracrystals).

Physical properties

Appearance: needlelike crystals were produced when recrystallized by methanol. Solubility: soluble in chloroform, acetone, and ethanol. Melting point: 211– 216?°C.?Sulfate melting point of vinblastine is 284–285?°C; hydrochloric acid melting point of vinblastine is 244–246?°C (decomposes). Specific optical rotation: +42°.

Originator

Velban ,Lilly ,US ,1961

The Uses of VINBLASTINE

Vinblastine is used for severe lymphoblastic leukemia, Hodgkin’s disease, nonHodgkin’s lymphoma, neuroblastoma, sarcoma, and other cancerous diseases.

The Uses of VINBLASTINE

Labelled Vinblastine (V314000). Antitumor alkaloid isolated from periwinkle, Vinca rosea Linn., Apocynaceae; inhibits microtubule assembly. An antineoplastic.

What are the applications of Application

Vinblastine is inhibits microtubule formation and suppresses nAChR activity

Background

Antitumor alkaloid isolated from Vinca rosea. (Merck, 11th ed.)

Indications

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

Indications

It was recorded in the Pharmacopoeia of the People’s Republic of China (2015), the British Pharmacopoeia (2017), the United States Pharmacopeia (40), the Japanese Pharmacopoeia (17th ed.), the European Pharmacopoeia (9th ed.), and The International Pharmacopoeia (5th ed.).
Vinblastine sulfate injection is used as the first-line therapy to treat Hodgkin lymphoma, lymphocytic leukemia, testis tumor, and choriocarcinoma intravenously in clinical practice generally according to ABVD methods (Adriamycin, bleomycin, vinblastine, and dacarbazine).

Manufacturing Process

According to US Patent 3,225,030, 1,500 grams of dried ground plant of Vinca rosea were intimately mixed with 1,000 ml of a 2% tartaric acid solution, and the mixture was extracted with three 9-liter portions of benzene. The benzene extracts were combined and were concentrated in vacuo to about 1,500 ml. The concentrate was mixed with 1 liter of 2% tartaric acid and the mixture was steam-distilled under reduced pressure until all of the benzene had distilled over. The insoluble residue was dissolved in hot methanol, a second 1-liter portion of 2% tartaric acid solution was added, and the mixture was steam-distilled under reduced pressure until all of the methanol had distilled.
The undistilled aqueous tartaric acid solution was extracted with three 1-liter portions of ethylene dichloride, and was then brought to a pH of about 8.5 to 9.5 by the addition of 28% aqueous ammonium hydroxide. The ammoniacal solution was extracted with three 1-liter portions of ethylene dichloride; the ethylene dichloride extracts were combined, were dried, and were evaporated in vacuo, yielding a residue of 3.35 grams of a light-brown powder.
1 1/2 grams of the residue were dissolved in 10 ml of benzene, and the solution was passed over a chromatographic adsorption column containing 50 grams of alumina (Alcoa activated alumina, Grade F-20) which had previously been shaken for about 20 minutes with a mixture of 100 ml of benzene containing 1.5 ml of 10% acetic acid.
The column was developed by washing it with 2,100 ml of benzene. The column was then washed sequentially with 300 ml of benzene-chloroform solvent (95:5 by volume) and 800 milliliters of benzene-chloroform solvent (75:25) to remove indeterminate impurities. The leurosine was eluted from the alumina by passing over the column 900 ml of benzene chloroform solvent (50:50).
The eluate was evaporated to dryness in vacuo, leaving an amorphous residue of 113 mg of leurosine. The residue was treated with a few ml of methanol in which it quickly dissolved, but from which leurosine quickly precipitated in crystalline form. Because of the affinity of leurosine for water, and the presence of traces of water in the solvents, the leurosine was obtained in the form of its octahydrate. Although the material as obtained was substantially pure, it was further purified by recrystallizing it from hot methanol solution. The hydrated leurosine obtained decomposed at about 200° to 205°C.
Further elution of the above chromatographic column with a 50:50 benzene- chloroform solvent mixture or with a 25:75 benzene-chloroform solvent mixture serves to elute vincaleukoblastine. Vincaleukoblastine also occurs in the latter fractions containing leurosine. Vincaleukoblastine is obtained from vincaleukoblastine-containing fractions by evaporation to dryness, either of a filtrate from which leurosine has previously been isolated, or from a chromatographic eluate fraction. The resulting residue is dissolved in ethanol and 286 ethanolic sulfuric acid is added until the pH is lowered to about 4. The solution is seeded with crystals of vincaleukoblastine sulfate and is chilled for about 24 hours. Vincaleukoblastine sulfate, if present, precipitates during this period and can be separated by filtration. Vincaleukoblastine sulfate melts at about 284° to 285°C.

brand name

Velban (Lilly).

Therapeutic Function

Cancer chemotherapy

Mechanism of action

Vinblastine suppresses cell growth during metaphase, affects amino acid metabolism, in particular at the level of including glutamine acid into the citric acid cycle and preventing it from transformation into urea, and it also inhibits protein and nucleic acid synthesis.

Pharmacokinetics

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.

Pharmacokinetics

Leukopenia is the dose-limiting side effect, and dose reductions are warranted in patients with serum bilirubin levels greater than 3 mg/dL. The drug-related impact on erythrocyte and thrombocyte levels usually is insignificant. Like vincristine, it is administered as an IV bolus or infusion. The initial elimination half-life of 3.7 minutes is similar to vincristine, but the 24.8-hour terminal half-life is significantly shorter.

Clinical Use

In addition to the hematologic indications that it shares with vincristine, vinblastine sulfate has found utility in the treatment of advanced testicular carcinoma (often in combination with bleomycin), advanced mycosis fungoides, Kaposi's sarcoma, and histiocytosis X.

Metabolism

Hepatic. Metabolism of vinblastine has been shown to be mediated by hepatic cytochrome P450 3A isoenzymes.