Epirubicin is also capable of generating cytotoxic free radicals, which are very reactive against DNA, cell membranes and mitochondria.Epirubicin exhibits activity in all phases of the cell cycle, but maximal cell kill occurs during the S and G2 phases of the cell cycle. Pharmacokinetics
The pharmacokinetic properties of epirubicin can be described by a 3-compartment model, with half-lives for the initial (alpha), intermediate (beta) and terminal (gamma) elimination phases of approximately 3 minutes, 1 hour and 30 hours, respectively. Only the latter differs substantially compared to doxorubicin, as the terminal elimination half-life of doxorubicin is estimated to be approximately 40-70% longer than that of epirubicin. The pharmacokinetics of epirubicin appear to be linear for doses in the range of 40 – 150 mg/m2.The volume of distribution of epirubicin is found to be high and variable (1 000- 1 500), but similar to those reported for doxorubicin. This indicates extensive distribution into the tissue. The total plasma clearance of epirubicin is approximately 45 to 50 L/h/m2, which is almost 2-fold higher than that of doxorubicin. Area under the plasma concentration versus time curve values (adjusted for dose) are 1.3 to 1.7 times higher for doxorubicin than epirubicin following single-dose intravenous administration. Epirubicin shows a 77% binding to plasma proteins, predominantly albumin, which is not affected by drug concentration. Metabolism
Epirubicin is rapidly metabolized by the liver to relatively or totally inactive metabolites: epirubicinol, 2 glucuronides and 4 aglycones.
The reduction to alcohol is performed with a derivative of a borohydride of an alkali metal with formula MHBL3, where M=Li, Na, K; L=AlkO, AlkCOO, ArCOO. The subsequent halogenation is performed with a complex halogenating agent where an H or a chain of up to 4 carbons is combined with Cl, I or Br. The final hydrolysis is analogous to the one in the first pathway. Development history
The first trial of epirubicin in humans was published in 1980. Upjohn applied for approval by the U.S. Food and Drug Administration (FDA) in node-positive breast cancer in 1984, but was turned down because of lack of data. In 1999 Pharmacia (who had by then merged with Upjohn) received FDA approval for the use of epirubicin as a component of adjuvant therapy in node-positive patients. Patent protection for epirubicin expired in August 2007. == References ==