Pharmacokinetics and metabolism of epidoxorubicin and doxorubicin in humans.

Abstract

Pharmacokinetics of doxorubicin (DOX), epidoxorubicin (EPI), and their metabolites in plasma have been performed in eight patients receiving 40 to 56 mg/m2 of both anthracyclines as a bolus injection in two sequential cycles. Terminal half-life and volume of distribution appeared to be smaller in case of EPI, whereas plasma clearance and cumulative urinary excretion was larger in comparison to DOX. The major metabolite of DOX was doxorubicinol (Aol) followed by 7-deoxy-doxorubicinol (7d-Aolon). Metabolism to glucuronides was found in case of EPI only. The area under the curves (AUC) of the metabolites of EPI decreased in the order of the glucoronides E-glu greater than Eol-glu, 7d-Aolon greater than epirubicinol (Eol). The AUC of Eol was half of the value in its counterpart Aol. In the case of EPI, the AUC of 7d-Aolon was twice the level of that of the corresponding metabolite of DOX. The terminal half-lives of the cytostatic metabolites Aol and Eol were similar, but longer than the corresponding values of their parent drugs. Half-lives of the glucuronides (E-glu, Eol-glu) were similar to the half-life of their parent drug. 7d-Aolon had a somewhat shorter half-life in comparison to both DOX and EPI. Approximately 6.2% of EPI and 5.9% of DOX were excreted by the kidney during the initial 48 hours. Aol was found in the urine of patients treated with DOX, whereas Eol, E-glu, and Eol-glu were detected in urine of patients treated with EPI. The cumulative urinary excretion appeared to be 10.5% for EPI and its metabolites, and 6.9% for DOX and its metabolite. The plasma concentration v time curves of (7d)-aglycones showed a second peak between two and 12 hours after injection, suggesting an enterohepatic circulation for metabolites lacking the daunosamine sugar moiety. The plasma concentrations of the glucuronides were maximal at 1.2 hours for E-glu and 1.9 hours for Eol-glu. All other compounds reached their maximum plasma concentration during the first minutes after the administration of DOX and EPI. Deviating plasma kinetics were observed in one patient, probably due to prior drug administration.

Prediction of response to docetaxel by CYP3A4 mRNA expression in breast cancer tissues

“…This observation seems to be explained by the fact that the antineoplastic effect of CE treatment is mostly attributable to epirubicin, and epirubicin is not metabolized by CYP3A4, 14 whereas cyclophosphamide is partly metabolized by CYP3A4. 15 Thus, the association between response and intratumoral CYP3A4 mRNA expression is considered to be specific to DOC, which is metabolized by CYP3A4.…”

Phase I clinical trial and pharmacokinetic evaluation of NK911, a micelle-encapsulated doxorubicin

“…These observations may be attributed to the fact that DXR was difficult to detect at 168 h after dosing at levels of below 24 mg m À2 , possibly resulting in an underestimation or an overestimation of the tails of the clearance curve. The half-lives (t 1/2a , t 1/2b , and t 1/2g ) were longer for NK911 than for free DXR (Mross et al, 1988). The AUC of NK911 was twofold larger than that of free DXR at a dose of 50 mg m À2 .…”

A monoclonal antibody-β-glucuronidase conjugate as activator of the prodrug epirubicin-glucuronide for specific treatment of cancer

“…We showed that the prodrug Epi-glu is 100-1,000 times less toxic than Epi and can be completely hydrolysed by the GUS-MAb conjugate bound to tumour cells into the active cytotoxic Epi is an active anti-tumour agent in patients with breast cancer, lymphomas, ovarian cancer, and soft-tissue sarcomas (Cersosimo & Ki Hong, 1986). Epi-glu is a naturally occurring metabolite in patients treated with Epi and the pharmacokinetics are well known (Mross et al, 1988). We used Epi-glu as a model prodrug.…”