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High intraliposomal doxorubicin concentration and intraliposomal acidic pH are the two critical factors that protect DXR in Doxil from UV-A degradation.

Epirubicin, in vivo and in vitro Interaction, Erythrocytes, Plasma Proteins In this study, the in vitro interaction of epirubicin (EPR), a cytostatic antibiotic, with plasma proteins (PP), namely a-HSA, y-HSG, a + ß-HSG and with isolated human red blood cells (RBCs) was investigated and further correlated with the in vivo pharmacokinetics and binding of EPR and two of its metabolites, 13-dihydroepirubicin and 7-deoxydoxorubicinone to RBCs. The in vitro encapsulation rate in isolated erythrocytes amounts to 52.9 ± 2.8% and remains constant within the range of studied concentrations (2.5-20 jo,g/ml). EPR was found to bind differently to the various PP in vitro. Binding to a-HSA amounted up to 51.0 ± 7.10%, to a + ß-HSG 79.45 ± 2.7%, to y-HSG 57.1 ± 2.8%. The in v/vo-binding rate of EPR, dihydroepirubicin and deoxydoxorubicinone to RBCs after 5 min of injection was 32 ± 6.96%, 11.6 ± 3.1% and 10.05 ± 3.5% respectively, their availability in serum was 42.6 ± 11.8%, 2.4 ± 0.4% and 1.2 ± 0.67% respectively. In tro d u ctio nSince it is know n th a t plasm a p roteins can play an effective role as a su b com p artm en t of the blood, it will be extrem ely useful to study the protein bind ing of drugs in o rd e r to o b tain fu rth er inform ation ab o u t its clinical pharm acokinetics and drug distri b ution (C olom bo et al., 1983). B lood com ponents m ay also function as a storage vehicle for drugs, ery throcytes for exam ple possess desirable p roperties of a drug carrier through w hich an intravasal dep o t m ay be achieved (P itt et al., 1983). Epirubicin, a cytostatic antibiotic from th e anthracycline family rep resents the 4 '-ep im er of doxorubicin. The m ech anism of its an titu m o r activity is sim ilar to th at of doxorubicin which in tercalates into D N A and blocks th erefo re p ro tein synthesis (Yoa-Pu H u et al., 1989) or inhibits the activity of the D N A topoisom erase II (Le B ot et al., 1988). E P R seem s to have a b e tte r therap eu tic index than doxorubicin, due to its low er m yelosuppressive and low er cardiotoxic effects at equal doses (W eenen et al., 1986). This can be explained by the Reprint requests to Mag. Suzan Bandak. Telefax: 0043-1-3107210. difference in pharm acokinetics and m etabolism revealing a low er half-life of elim ination for E P R due to a unique glucuronidation pathw ay in hum an (Van d er Vigh et al., 1990). D ue to the fact th at R BCs play an active role in drug distribution, m etabolism and elim ination it was necessary to carry out this study to investigate how far R B C s do interfere in the distribution and m etabolism of E PR . The m echanism of interaction betw een E P R and R B C s m ight be an electrostatic one, sim ilar to th at of doxorubicin (Suillerot et al., 1988) and/or interaction with the lipid com ponents of the R B C m em brane. The fact th a t m etabolites were found in RB C s indicates p en etratio n of E P R inside the RB C s and thus supposing the presence of lipid areas inside the blood cells.Two m etabolites w ere detected with the system ...

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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 compartiment distinctly faster in compare to the control, when QUI was preadministered (t1/2 = 6 min for the control group and t1/2 = 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 9.5 h for the control group and 8.6 h for the QUI group (-10% ). The mean initial serum concentration (c0) 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 AUC0-24-values) from 3404 ± 1008 ng/ml × h to 2359 ± 1073 ng/ml × h (-3 1 % , p < 0.05). Vd and Vdß were increased at about 90% and the mean total body clearance was accelerated from 45.3 to 148.7 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 kRBC of EPR was lower if QUI was coadministered (kRBC = 1.25 ± 0.12 for the control group kRBC = 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.