Epirubicin

The mechanism of action of epirubicin hydrochloride is related to its ability to bind to DNA. Cell culture studies have shown rapid cell penetration, localisation in the nucleus and inhibition of nucleic acid synthesis and mitosis.

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

In patients with normal hepatic and renal function, plasma levels after I.V. injection of 60-150 mg/m² of the drug follow a tri-exponential decreasing pattern with a very fast first phase and a slow terminal phase with a mean half-life of about 40 hours. These doses are within the limits of pharmacokinetic linearity both in terms of plasma clearance values and metabolic pathway. The major metabolites that have been identified are epirubicinol (13-OH epirubicin) and glucuronides of epirubicin hydrochloride and epirubicinol.

The 4'-O-glucuronidation distinguishes epirubicin hydrochloride from doxorubicin and may account for the faster elimination of epirubicin hydrochloride and its reduced toxicity. Plasma levels of the main metabolite, the 13-OH derivative (epirubicinol) are consistently lower and virtually parallel those of the unchanged drug.

Epirubicin hydrochloride is eliminated mainly through the liver; high plasma clearance values (0.9 l/min) indicate that this slow elimination is due to extensive tissue distribution.

Urinary excretion accounts for approximately 9-10% of the administered dose in 48 hours.

Biliary excretion represents the major route of elimination, about 40% of the administered dose being recovered in the bile in 72 hours. The drug does not cross the blood brain barrier.

The main target organs in rat, rabbit and dog following repeated dosing were the haemolymphopoietic system, GI tract, kidney, liver and reproductive organs.

Epirubicin hydrochloride was also cardiotoxic in the species tested.

It was genotoxic, and, like other anthracyclines, carcinogenic in rats.

Epirubicin hydrochloride was embryotoxic in rats. No malformations were seen in rats or rabbits, but like other anthracyclines and cytotoxic drugs, epirubicin hydrochloride must be considered potentially teratogenic.

A local tolerance study in rats and mice showed extravasation of epirubicin hydrochloride causes tissue necrosis.