Pharmacokinetic interaction between 4'-epidoxorubicin and the multidrug resistance reverting agent quinine.
The serum and red blood cell (RBCs) disposition of epirubicin (EPR) after intravenous bolus injection without and with coadministered quinine ( QUI) was investigated in patients undergoing a cyclic chemotherapy with EPR. QUI possesses a statistical significant influence on the EPR serum concentrations and, as a consequence, on the pharmacokinetic parameters for the initial distribution phase of EPR. Within the first 15 min after administration, EPR was distributed from the central compartment distinctly faster in compare to the control, when QUI was preadministered (t(1/2) = 6 min for the control group and t(1/2) = 3 min with QUI; -46%, p < 0.05). Yet, in the beta-phase when drug-elimination predominates, no statistical significant influence of QUI in regard to EPR serum and RBC concentrations could be observed. Half-life of elimination was 0.5 h for the control group and 8.6 h for the QUI group (-10%). The mean initial serum concentration (co) was reduced significantly by QUI from 7359 +/- 506 ng/ml to 4351 +/- 1682 ng/ml (-42%, p < 0.005). Furthermore, QUI caused a reduction of the serum bioavailability of EPR (expressed as AUC(o-24)-values) from 3404 +/- 1008 ng/ml x h to 2359 +/- 1073 ng/ml x h (-31%, p < 0.05). Vd and Vdbeta were increased at about 90% and the mean total body clearance was accelerated from 45.3 to 1487 ml/min, but due to the large standard deviations the calculated difference for these parameters was not statistically significant. In the observed time interval of 24 h, the red blood cell coefficient of distribution k(rbc) of EPR was lower if QUI was coadministered (k(rbc) = 1.25 +/- 0.12 for the control group k(rbc) = 1.15 +/- 0.13 under QUI; p < 0.04). The results point out that QUI induces an accelerated distribution of EPR from the blood into the tissue and that QUI additionally may have influence on the red-blood cell partitioning of EPR.
Czejka
M
M
Institut für Pharmazeutische Chemie, Pharmaziezentrum der Universität Wien, Osterreich.
Bandak
S
S
Simon
D
D
Schüller
J
J
Weiss
C
C
Schernhammer
E
E
D000903:Antibiotics, Antineoplastic / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000097:blood* / Q000188:drug therapy*; D018432:Drug Resistance, Multiple; D015251:Epirubicin / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006801:Humans; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D011803:Quinine / Q000494:pharmacology*
D000903:Antibiotics, Antineoplastic; D015251:Epirubicin; D011803:Quinine