Fludarabine phosphate

Bezeichnung:Fludarabine phosphate

CAS-Nr75607-67-9

Englisch Name:Fludarabine phosphate

CBNumberCB7347825

SummenformelC10H13FN5O7P

Molgewicht365.21

MOL-Datei75607-67-9.mol

Fludarabine phosphate physikalisch-chemischer Eigenschaften

Schmelzpunkt	203°C(dec.)(lit.)
alpha	[α]D20 +10～+14゜(c=0.5,H2O)
Siedepunkt	864.2±75.0 °C(Predicted)
Dichte	2.39±0.1 g/cm3(Predicted)
RTECS-Nr.	UO7440900
storage temp.	2-8°C
Löslichkeit	DMSO: soluble1mg/mL
pka	1.86±0.10(Predicted)
Aggregatzustand	Powder
Farbe	white
Wasserlöslichkeit	Soluble in DMSO or water at 5mg/ml
Merck	14,4126
Stabilität	Hygroscopic
InChIKey	GIUYCYHIANZCFB-GFRUICAKSA-N
CAS Datenbank	75607-67-9(CAS DataBase Reference)

Sicherheit

WGK Germany	3
HS Code	2934990002

Gefahreninformationscode (GHS)

Fludarabine phosphate Chemische Eigenschaften,Einsatz,Produktion Methoden

Beschreibung
Fludarabine phosphate is an antimetabolite indicated for the treatment of B cell lymphocytic leukemia. It is reportedly effective in patients refractory to other therapies. Fludarabine phosphate acts by inhibiting primer RNA synthesis. Its side effects include bone marrow suppression, anemia, thrombocytopenia and neutropenia.
Chemische Eigenschaften
White or almost white, crystalline powder, hygroscopic.
Originator
Southern Research Institute (U.S.A.)
Verwenden
Fludarabine phosphate is used for the treatment of chronic lymphatic leukemia and low-grade lymphoma. In the circulation,fludarabine phosphate is immediately dephosphorylated to the nucleoside fludarabine. About 30-40% of nucleoside fludarabine is excreted into the urine. In addition, fludarabine is metabolized into a hypoxanthine metabolite also excreted in the urine.Intracellularly,fludarabine is stepwise rephosphorylated to the active triphosphate. Deoxycytidine kinase is the dominant, if not the exclusive,enzyme for the formation of the monophosphate. Adenylate kinase and nucleoside diphosphate kinase are believed to be involved in the formation of the diphosphate and triphosphate,respectively.
Verwenden
anticonvulsant
Definition
ChEBI: Fludarabine phosphate is a purine arabinonucleoside monophosphate having 2-fluoroadenine as the nucleobase. A prodrug, it is rapidly dephosphorylated to 2-fluoro-ara-A and then phosphorylated intracellularly by deoxycytidine kinase to the active triphosphate, 2-fluoro-ara-ATP. Once incorporated into DNA, 2-fluoro-ara-ATP functions as a DNA chain terminator. It is used for the treatment of adult patients with B-cell chronic lymphocytic leukemia (CLL) who have not responded to, or whose disease has progressed during, treatment with at least one standard alkylating-agent containing regimenas. It has a role as an antimetabolite, an antineoplastic agent, an immunosuppressive agent, an antiviral agent, a prodrug and a DNA synthesis inhibitor. It is an organofluorine compound, a nucleoside analogue and a purine arabinonucleoside monophosphate. It derives from a 2-fluoroadenine.
Trademarks
Fludara (Berlex), Benefluor (Schering AG).
Mechanism of action
Fludarabine phosphate is a cytotoxic purine antimetabolite that acts by inhibiting DNA synthesis. Fludarabine and its soluble derivatives interfere with phosphorylation, e.g., in L 1210 cells. Fludarabine behaves more like an analog of deoxycytidine than adenine or deoxyadenine as indicated by reports demonstrating that the presence of fluorine in the 2-position of the adenine ring alters its function as a substrate for deaminase and nucleoside kinases. This results in differences in biological activity and metabolism. Halogenation does not simply block deamination, but also influences the enzyme that carries out the phosphorylation, as a result cytotoxicity is increased. Fludarabine phosphate may selectively inhibit the incorporation of thymidine and uridine into the DNA molecule by inhibiting both ribonucleotide reductase and DNA polymerase. The maximum tolerated dose (MTD) in heavily pretreated patients with advanced malignancy/solid tumors on the daily regimen was about 15 mg/m2. Granulocytopenia and thrombocytopenia were dose-limiting.
Pharmakologie
Fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-ara-A and then phosphorylated intracellularly by deoxycytidine kinase to the active triphosphate, 2-fluoro-ara-ATP. This metabolite appears to act by inhibiting DNA polymerase alpha, ribonucleotide reductase and DNA primase, thus inhibiting DNA synthesis. The mechanism of action of this antimetabolite is not completely characterized and may be multi-faceted.
Phase I studies in humans have demonstrated that fludarabine phosphate is rapidly converted to the active metabolite, 2-fluoro-ara-A, within minutes after intravenous infusion.
Consequently, clinical pharmacology studies have focused on 2-fluoro-ara-A pharmacokinetics. After the five daily doses of 25 mg 2-fluoro-ara-AMP/m2 to cancer patients infused over 30 minutes, 2-fluoro-ara-A concentrations show a moderate accumulation. During a 5-day treatment schedule, 2-fluoro-ara-A plasma trough levels increased by a factor of about 2. The terminal half-life of 2-fluoro-ara-A was estimated as approximately 20 hours. In vitro, plasma protein binding of fludarabine ranged between 19% and 29%.
Clinical Use
Fludarabine phosphate (Fludara ® ), is a fluorinated nucleotide analog of the antiviral agent vidarabine, 9-β-D-arabinofuranosyladenine(ara-A), which differs only by the presence of a fluorine atom at position 2 of the purine moiety and a phosphate group at position 5 of the arabinose moiety (Plunkett et al., 1993). These structural modifications result in increased aqueous solubility and resistance to enzymatic degradation by adenosine deaminases compared to vidarabine (Brockman et al., 1977; Plunkett et al., 1990). Fludarabine phosphate is indicated for the treatment of patients with B-cell chronic lymphocytic leukemia (CLL) who have not responded to or whose disease has progressed during treatment with at least one standard alkylating agent containing regimen (Boogaerts et al., 2001; Rossi et al., 2004).
target
DNA synthesis
Arzneimittelwechselwirkung
Potentially hazardous interactions with other drugs
Antipsychotics: avoid concomitant use with clozapine, increased risk of agranulocytosis.
Cytotoxics: increased pulmonary toxicity with pentostatin (unacceptably high incidence of fatalities); increases intracellular concentration of cytarabine.
Stoffwechsel
Intravenous fludarabine phosphate is rapidly dephosphorylated to fludarabine which is taken up by lymphocytes and rephosphorylated via the enzyme deoxycytidine kinase to the active triphosphate nucleotide. Clearance of fludarabine from the plasma is triphasic; elimination is mostly via renal excretion: 40-60% of an intravenous dose is excreted in the urine. The pharmacokinetics of fludarabine show considerable inter-individual variation

Fludarabine phosphate Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

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