Pharmacokinetics and cerebrospinal fluid penetration of daunorubicin, idarubicin, and their metabolites in the nonhuman primate model.
OBJECTIVE
Idarubicin (4-demethoxy-daunorubicin) is more potent and less cardiotoxic than the commonly used anthracyclines, doxorubicin and daunorubicin. In addition, idarubicin is metabolized to an active metabolite, idarubicinol, in contrast to other anthracyclines whose alcohol metabolites are much less active than the parent drug. The current study was performed in nonhuman primates to determine the plasma and cerebrospinal fluid (CSF) pharmacokinetics of idarubicin and idarubicinol and to compare them to the pharmacokinetics of daunorubicin and daunorubicinol.


METHODS
A dose of 30 mg/m2 of daunorubicin or 8 mg/m2 of idarubicin was administered intravenously over 15 minutes. Plasma and CSF were sampled frequently from the end of the infusion to 72 to 96 hours after infusion. Drug and metabolite concentrations were measured using high-pressure liquid chromatography (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 (AUC) 22.5 +/- 9.2 mumol/L.min, and clearance 2790 +/- 960 mL/min/m2. Daunorubicinol elimination was biphasic with a terminal half-life 10.2 +/- 2.3 hours and an AUC 74.5 +/- 5.3 mumol/L.min. Idarubicin elimination was triphasic with terminal half-life of 12.3 +/- 11.4 hours, a AUC 10.8 +/- 3.7 mumol/L.min, and clearance 1650 +/- 610 mL/min/m2. Idarubicinol elimination was biphasic with a terminal half-life 28.7 +/- 4.2 hours and AUC 67 +/- 9.8 mumol/L.min. CSF penetration was low for both parent drugs and their metabolites. CSF idarubicin was measurable at a single time point (1 hour 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 animal and 15% in the other. Idarubicinol was detected in 2 to 4 samples at various 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 corresponding time points was 1.9 +/- 0.6%. Daunorubicin was measurable for < 6 hours 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 detectable at 24 hours in 2 of 3. The terminal half-life of daunorubicinol in CSF was 8.8 +/- 1.3 hours, the AUC was 1.8 +/- 1.5 mumol/L.min, and the AUCCSF to AUCplasma ratio was 2.4 +/- 1.9%.


CONCLUSIONS
Idarubicin, idarubicinol, daunorubicin, and daunorubicinol penetrate poorly into the CSF after intravenous administration.
Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine Houston, USA.
S L
SL
Berg
J
J
Reid
K
K
Godwin
D J
DJ
Murry
D G
DG
Poplack
F M
FM
Balis
M M
MM
Ames
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D003630:Daunorubicin / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D015255:Idarubicin / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D008253:Macaca mulatta; D008297:Male
D000903:Antibiotics, Antineoplastic; D015255:Idarubicin; D003630:Daunorubicin