Amrubicin

483.47

483.47

93N13LB4Z2

C80089

L - Antineoplastic and immunomodulating agents

176.61000

2.64

1.60±0.1 g/cm3(Predicted)

172-1740C

717.8±60.0 °C(Predicted)

387.9±32.9 °C

1.720

not soluble in water, but soluble in DMSO

D20 +119° (c = 0.02 in CHCl3)

Based on acute intravenous dose toxicity studies, the lethal dose to 50% of animals was estimated to be 42 mg/kg in mice, 14 mg/kg in rats, and 4 mg/kg in dogs. Myelosuppression, with the primary clinical manifestation of neutropenia and leucopenia, is the dose-limiting toxicity of this drug. In addition to this, mucositis, nausea, vomiting, and alopecia are frequent. Hepatopathy, observed with elevated bilirubin concentrations, occurs less frequently. Cardiotoxicity is a major adverse effect of the anthracycline antibiotics and may be acute or chronic; in the acute setting, electrocardiographic (ECG) abnormalities may be observed, demonstrating ST-T elevations and arrhythmias, however, chronic cardiotoxicity poses a serious risk that may be lethal due to the slow development of irreversible, cardiomyopathy. The occurrence of toxicity shows a significant interindividual variation, and for this reason, the pharmacokinetics and pharmacodynamics of anthracyclines have been heavily investigated in order to identify models that may be used in the clinical setting to prevent the development of serious toxicity, mainly leucopenia, and maximize tumor exposure. Interestingly, a recent study was done to further examine genetic predisposition neutropenia/amrubicin toxicity. It was determined that C3435T polymorphisms of the ABCB1 gene might be able to predict severe amrubicin-induced neutropenia. Secondary alcohol metabolites of earlier generation anthracyclines have been shown to lead to cardiac toxicity which is a major toxicity of conventional anthracyclines and thus limits the amount that can be delivered safely to patients. Clinical manifestations of toxicity observed on the acute and repeated administration of amrubicin in rats and dogs were dose-related and reversible including fecal changes (mucoid or bloody feces/diarrhea), body weight decreases, decreased food consumption, decreased activity, and alopecia. Similar findings were observed at doses of doxorubicin approximately one half those of amrubicin.

A study was performed on the plasma protein binding of amrubicin in both patients with hepatic impairment and those with normal liver function. In those with liver impairment, the plasma protein binding was found to be 91.3–97.1% and in those with normal hepatic function, 82.0–85.3%.

Investigated for use/treatment in lung cancer.

The _anthracycline glycoside_ group of antibiotics, which includes amrubicin, represent a group of potent anticancer agents with potent activity against both solid tumors and hematological malignancies. They are the principal subjects of a large number of studies for the treatment of adult and childhood neoplastic diseases. Amrubicin is a 9-aminoanthracycline derivative and promotes cell growth inhibition by stabilizing protein – DNA complexes followed by double-stranded DNA breaks, which are mediated by topoisomerase-II enzyme. Anthracyclines have been observed to have a variety molecular effects (for example, DNA intercalation, inhibition of topoisomerase II, and stabilization of topoisomerase IIα cleavable complexes). Amrubicin shows decreased DNA intercalation when compared with doxorubicin. The decreased DNA interaction likely influences the intracellular distribution because amrubicin and its metabolite, _amrubicinol_. Amrubicin showed 20% distribution into the nucleus of P388 cells compared with the 80% nuclear distribution shown by doxorubicin (another anthracycline drug). The cell growth inhibitory effects of amrubicin appear to be mainly due to the inhibition of topoisomerase II.

Substances that inhibit or prevent the proliferation of NEOPLASMS. (See all compounds classified as Antineoplastic Agents.)

Peak plasma concentrations of the active metabolite _amrubicinol_ were observed from immediately after administration of amrubicin to 1h after administration. Plasma concentrations of amrubicinol were low compared with amrubicin plasma concentrations. The plasma amrubicinol AUC (area under the curve) was approximately 10-fold lower than the amrubicin plasma AUC. Concentrations of amrubicinol were higher in RBCs as compared with plasma. Amrubicinol AUCs ranged from 2.5-fold to 57.9-fold higher in red blood cells (RBCs) compared to plasma. Because amrubicinol distributes itself into RBCs more than amrubicin, the concentrations of amrubicinol and amrubicin in RBCs were quite similar. The AUC of amrubicinol in RBCs was approximately twofold lower than the amrubicin RBC AUC. In one study, after repeated daily amrubicin administration, amrubicinol accumulation was observed in plasma and RBCs. On day 3, the amrubicinol plasma AUC was 1.2-fold to 6-fold higher than day 1 values; the RBC AUC was 1.2-fold to 1.7-fold higher than day 1 values. After 5 consecutive daily doses, plasma and RBC amrubicinol AUCs were 1.2-fold to 2.0-fold higher than day 1 values.|In one study, urinary excretion of amrubicin and amrubicinol after ingestion of amrubicin accounted for 2.7% to 19.6% of the administered dose. The amount of excreted amrubicinol was approximately 10-fold greater than excreted amrubicin. Excretion of amrubicin and its metabolites is primarily hepatobiliary. Enterohepatic recycling was demonstrated in rats.|Moderate volume of distribution (1.4 times total body water).|The plasma pharmacokinetics of amrubicin in cancer patients are characterized by low total clearance (22% of total liver blood flow).

The primary metabolite (amrubicinol) in rats and dogs is a product of reduction by cytoplasmic carbonyl reductase at the C-13 carbonyl group. Other enzymes participating in the metabolism of amrubicin and amrubicinol were nicotinamide adenine dinucleotide phosphate, reduced form (NADPH)–P450 reductase and nicotinamide adenine dinucleotide [phosphate] (NAD[P]H)-quinone oxidoreductase. Twelve additional metabolites were detected in vivo and in vitro in one study. Peak plasma concentrations of the active metabolite amrubicinol were observed from immediately after dosing to 1 hour after dosing. These included four aglycone metabolites, two amrubicinol glucuronides, deaminated amrubicin, and five highly polar unknown metabolites. In vitro cell growth inhibitory activity of the minor metabolites was substantially lower than that of amrubicinol. Excretion of amrubicin and its metabolites is primarily hepatobiliary. Enterohepatic recycling was demonstrated in rats.

20-30 h In a study of dogs, Amrubicin plasma concentrations followed a biphasic pattern with peak concentrations observed immediately after dosing followed by α and β half-lives (t1/2) ± SD of 0.06 ± 0.01 and 2.0 ± 0.3 hours, respectively.

As an anthracycline, amrubicin has antimitotic and cytotoxic activity through a variety of mechanisms of action. Amrubicin is found to form complexes with DNA via intercalation between base pairs, and it inhibits topoisomerase II enzyme activity by stabilizing the DNA-topoisomerase II complex, which prevents the re-ligation portion of the ligation-religation reaction that topoisomerase II normally catalyzes. Topoisomerase II is an enzyme located in the nucleus that regulates DNA structure through double-strand breakage and re-ligation, therefore modulating DNA replication and transcription. Inhibition of the enzyme leads to inhibition of DNA replication and halt cell growth with an arrest of the cell cycle occurring at the G2/M phase. The mechanism by which amrubicin inhibits DNA topoisomerase II is believed to be through stabilization of the cleavable DNA–topo II complex, ending in re-ligation failure and DNA strand breakage. DNA damage triggers activation of caspase-3 and -7 and cleavage of the enzyme PARP (Poly ADP ribose polymerase), leading to apoptosis and a loss of mitochondrial membrane potential. Amrubicin, like all anthracyclines, intercalates into DNA and produces reactive oxygen free radicals via interaction with NADPH, which causes cell damage. Compared with doxorubicin, another member of the anthracycline drug class, amrubicin binds DNA with a 7-fold lower affinity and therefore, higher concentrations of amrubicin are necessary to promote DNA unwinding.

(+)-(7S,9S)-9-acetyl-9-amino-7-((2-deoxy-beta-d-erythro-pentopyranosyl)oxy)-6,11-dihydroxy-7,8,9,10-tetrahydrotetracene-5,12-dione hydrochloride