Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties

Antibiotic with a cytostatic effect belonging to the group of anthracyclines ATC code: L01D B03

Epirubicin is a 4’-epimer of the anthracycline antibiotic doxorubicin. Its pharmacological properties correspond to those of other anthracyclines. Epirubicin is active during all phases of the cell cycle and demonstrates maximum cytotoxic effects in the S and G2 phase of the cell cycle. The exact antineoplastic mode of action is not completely known, but is most likely based on its ability to form complexes with DNA by intercalating between DNA base pairs. This leads to steric inhibition of DNA and RNA synthesis.

The intercalation of epirubicin also appears to interfere with the topoisomerase DNA “cleavable complex”. Further modes of action presently discussed are the formation of free radicals, a direct membrane effect, as well as the formation of chelates with metal ions.

Epirubicin is active on a wide spectrum of experimental tumours including L1210 and P388 leukaemias, sarcoma SA180 (solid and ascitic forms), B16 melanoma, mammary carcinoma, Lewis lung carcinoma and colon carcinoma 38. It has also proved effective against human tumours transplanted into athymic nude mice (melanoma, mammary, lung, prostatic and ovarian carcinomas).

Pharmacokinetic Properties

5.2     Pharmacokinetic properties
Shortly after IV application, epirubicin concentrations are found in most tissues. In spite of the large volume of distribution of epirubicin, experimental tests on animals show that epirubicin crosses the blood-brain barrier only to a very limited extent.

Epirubicin plasma levels follow a tri-exponential decreasing pattern with a rapid initial distribution phase (t1/2: 3.0-4.8 minutes), followed by an intermediate elimination phase (t 1/2β: 1.1-2.6 hours) and a slow terminal phase of elimination (t1/2: 18 – 45 hours).

The volume of distribution (Vd) of epirubicin is 32 – 46 l/kg.
Plasma clearance ranges from 30 – 100 l/h.

Epirubicin is mainly metabolised in the liver. One active metabolite (epirubicinol) and 6 inactive metabolites (epirubicinol glucuronide, epirubicin glucuronide as well as 4 aglycones) have been identified. Epirubicinol demonstrates a ten times lower cytotoxic activity in vitro than epirubicin. No significant activity or toxicity could be detected for the other metabolites.

Approximately 6 – 7% of an administered dose is eliminated in unchanged form via the kidneys, less than 5% as glucuronides and even smaller amounts as epirubicinol. Following hepatic metabolisation, approx. 35% of an administered dose is eliminated via biliary excretion. The biliary and renal clearance are 8 – 33 and 4 – 15 l/h respectively.