Pharmacokinetics of erythrocyte-bound daunorubicin in patients with acute leukemia.
BACKGROUND
The objective of the present study was in vitro and in vivo investigation of erythrocytes as vehicles for anthracycline antibiotics.


METHODS
The kinetics of daunorubicin binding with erythrocytes was studied in blood and in washed erythrocyte suspensions from healthy donors and patients with acute leukemia. The effect of daunorubicin on erythrocyte deformability was studied using cell filtration through membranes with 3 microm-diameter cylindrical pores. Erythrocyte-bound daunorubicin (EBD), prepared by equilibrating anticoagulated autologous blood with the antibiotic, was administered (45 or 60 mg/m2 body surface) to 14 leukemic patients as part of the 7+ 3 or RACOP courses. The pharmacokinetics of daunorubicin and its tolerability were studied.


RESULTS
Human erythrocytes bound daunorubicin (rubomycin) in citrated whole blood or in washed saline suspension. The equilibrium erythrocyte/medium daunorubicin concentration ratios (attained in 30-60 min at 37 degrees C) averaged 2.9 +/- 0.5 (n=13) in blood and 5.7 +/- 0.6 (n=8) in suspension (p<0.001), without any significant difference between the erythrocytes of donors and patients with acute drug-resistant leukemia or leukemic relapses. Incubation of patient blood with daunorubicin (0.5 mg/ml cells) did not affect erythrocyte deformability (filterability). After intravenous administration, the peak drug concentration and its elimination rate were lower for EBD than for free daunorubicin. The patients tolerated EBD better than its standard free form. In nine patients who received three EBD infusions, side effects were less frequent than in those treated with free daunorubicin.


CONCLUSIONS
Our results indicate that daunorubicin-loaded erythrocytes are promising for clinical application and deserve further clinical study.
Skorokhod
Oleksli A
OA
National Research Center for Hematology, Russian Academy of Medical Sciences, Moscow, Russia.
Garmaeva
Tat'yana Ts
TTs
Vitvitsky
Victor M
VM
Isaev
Valentin G
VG
Parovichnikova
Elena N
EN
Savchenko
Valerii G
VG
Ataullakhanov
Fazoil I
FI
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003630:Daunorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004907:Erythrocyte Deformability / Q000187:drug effects; D004912:Erythrocytes / Q000378:metabolism*; D005260:Female; D006801:Humans; D007938:Leukemia / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged
D000903:Antibiotics, Antineoplastic; D003630:Daunorubicin