Pharmacokinetics and cerebrospinal fluid penetration of daunorubicin, idarubicin, and their metabolites in the nonhuman primate model

Purpose: Idarubicin (4-demethoxy-daunorubicin) is more potent and less card iotoxic than the commonly used anthracyclines, doxorubicin and daunorubicin . In addition, idarubicin is metabolized to an active metabolite, idarubici nol, in contrast to other anthracyclines whose alcohol metabolites are much less active than the parent drug. The current study was performed in nonhu man primates to determine the plasma and cerebrospinal fluid (CSF) pharmaco kinetics of idarubicin and idarubicinol and to compare them to the pharmaco kinetics of daunorubicin and daunorubicinol. Methods: A dose of 30 mg/m(2) of daunorubicin or 8 mg/m(2) of idarubicin wa s administered intravenously over 15 minutes. Plasma and CSF were sampled f requently from the end of the infusion to 72 to 96 hours after infusion. Dr ug and metabolite concentrations were measured using high-pressure liquid c hromatography (HPLC). Results: Daunorubicin elimination from plasma was triphasic with a terminal half-life of 5.9 +/- 1.8 hours, area under the concentration-time curve (A UC) 22.5 +/- 9.2 mu mol/L . min, and clearance 2790 +/- 960 mL/min/m(2). Da unorubicinol elimination was biphasic with a terminal half-life 10.2 +/- 2. 3 hours and an AUC 74.5 +/- 5.3 mu mol/L . min. Idarubicin elimination was triphasic with terminal half-life of 12.3 +/- 11.4 hours, a AUC 10.8 +/- 3. 7 mu mol/L min, and clearance 1650 +/- 610 mL/min/m(2). Idarubicinol elimin ation was biphasic with a terminal half-lift 28.7 +/- 4.2 hours and AUC 67 +/- 9.8 mu mol/L min. CSF penetration was low for both parent drugs and the ir metabolites. CSF idarubicin was measurable at a single time point (1 hou r after administration) for 2 animals, and was not measurable for the third . The CSF to plasma concentration ratio at that time point was 8% in 1 anim al and 15% in the other. Idarubicinol was detected in 2 to 4 samples at var ious times, appearing as early as 1 hour in 1 animal and persisting as late as 48 hours in another. The CSF to plasma concentration ratio at correspon ding time points was 1.9 +/- 0.6%. Daunorubicin was measurable for < 6 hour s after intravenous administration. For individual animals, the mean CSF to plasma concentration ranged from 4% to 12%. Daunorubicinol was detectable by 1 hour in 2 of 3 animals and by 3 hours in the other, and remained detec table at 24 hours in 2 of 3. The terminal half-life of daunorubicinol in CS F was 8.8 +/- 1.3 hours, the AUC was 1.8 +/- 1.5 mu mol/L . min, and the AU C(CSF) to AUC(plasma) ratio was 2.4 +/- 1.9%. Conclusion: Idarubicin, idarubicinol, daunorubicin, and daunorubicinol pene trate poorly into the CSF after intravenous administration.