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.

m.p.= 123-125 "C] from 11. 12 reacts with trimethyloxonium tetrafluoroborate to yield 3,6-bis[bis(methylthio)methylenel-1,4-dimethyl-2,5-bis(methylthio)3,6-dihydropyrazindium bis(tetrafluorob0rate) 13 [83%, orange needles, blackens above 225 "C; UV/VIS (CH,CN): A, , , (lgE)=205 (4.15), 300 (sh, 4.09), 447 nm (4.21)]. M e S K S M e M e S +SMe SMe 14 CN 17 Me S M e S K S M e 15 16 a : CH2C12, 25 "C, 15 h; b : CH2Cl2/H20, 25 "C, 2 h; c: CH,CN, 25 "C, 15 h; d : pyridine, A, 1 h. 13 contains two ambifunctional azaallyl cation moieties. Heating with malononitrile in pyridine gives the tetrakis(methy1ene)piperazine derivative 17 [80%, yellow needles, m.p.= 189.5-191 "C; UV/VIS (CH,CN): A, , , (lg E ) = 225 (4. lo), 274 (4.30), 360 nm (4.40)], and this is the product expected from the charge distribution in 13. The site at which malononitrile attacks the C atom of the C=N bonds is confirmed by the fact that the salt obtained from 12 and triethyloxonium fluoroborate also reacts with malononitrile to afford 17. In the same way, 13 reacts with sodium cyanide and sodium sulfide to yield 16 [29%, m. p. = 162.5-163 "C] and the episulfide 15 [57%, m.p. = 170.5-171 "C (decomp.)], respectively, which is interesting inter alia because of its structural relationship with the 3,6-epithio-2,5-piperazinediones (~f.[~]).Remarkably, sodium methanethiolate reacts with 13 to

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Epidoxorubicin, a stereoisomer of doxorubicin, shows comparable antitumor activity but diminished cardiotoxicity compared with the latter. To find a pharmacokinetic basis for the observed difference in cardiotoxicity between the drugs, concentrations of doxorubicin, epidoxorubicin and all known metabolites were measured in the plasma, heart and tumor tissue of BALB/c mice bearing colon-26 tumors. Both drugs were injected at the same dose (10 mg/kg) as an i.v. bolus. Plasma, heart and tumor samples were obtained from two mice sacrificed at regular intervals over 48 h. Plasma and tissue extracts were analyzed by HPLC with fluorescence detection. The parent compounds and the two 7d-aglycones were present in all three compartments, whereas doxorubicinol (Aol) and epidoxorubicinol (Eol) could only be detected in the plasma and heart. Half-lives and AUCs of doxorubicin and its metabolites were higher than the corresponding values for epidoxorubicin and its metabolites in all three compartments.

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