caa a22 4500 467946523 CHVBK 20180405193737.0 cr unu---uuuuu 170328e20040101xx s 000 0 eng 10.1007/s00280-003-0700-2 doi (NATIONALLICENCE)springer-10.1007/s00280-003-0700-2 (NATIONALLICENCE)springer-10.1007/BF02665354 Increased myelotoxicity of idarubicin: is there a pharmacological basis? [Elektronische Daten] Results of a pharmacokinetic and an in vitro cytotoxicity study [Frank Kroschinsky, Eberhard Schleyer, Ulf Renner, Claudia Schimming, Christoph Schimmelpfennig, Martin Bornhäuser, Thomas Illmer, Lorenz Trümper, Gerhard Ehninger, Markus Schaich] Background: Clinical trials evaluating idarubicin (IDA) in acute myeloid leukemia, multiple myeloma and non-Hodgkin's lymphoma (NHL) have provided some evidence for an increased myelotoxicity of IDA compared to other anthracyclines. IDA is known to be less sensitive towards multidrug resistance mediated by P-glycoprotein (P-gp). This phenotype is a major impediment to successful antineoplastic treatment, but P-gp is also expressed on hematopoietic stem cells (HSC). Methods: We investigated the pharmacokinetics of IDA and etoposide (ETO) in seven previously untreated patients with aggressive NHL. The patients received a CHOP-derived protocol (CIVEP) in which doxorubicin (DOX) was substituted by IDA 11-16mg/m2 and ETO 3×100mg/m2 was added. Furthermore, we evaluated in vitro the impact of P-gp expression on the cytotoxicity of DOX and IDA in cells from three parental chemosensitive leukemia and lymphoma cell lines (HL60, U937, CCRF) and their resistant sublines, as well as in CD34-positive HSC. Results: The peak plasma levels (Cmax), terminal elimination half-life (t1/2) and area under the concentration curve (AUC) both for IDA and for ETO did not differ from published data. In cell line models the numbers of viable cells in a P-gp-expressing resistant CCRF-VCR100 subline were significantly more reduced by IDA (P<0.001), but there was no difference in the cytotoxicities of IDA and DOX in chemosensitive CCRF cells and in the (non-P-gp-expressing) resistant U937 and HL60 sublines. Cytotoxicity against HSC was more pronounced after incubation with IDA than after treatment with DOX (P=0.014), even when a tenfold higher concentration of DOX than of IDA was used. The addition of cyclosporin A increased the cytotoxic effect of DOX but not that of IDA in HSC. Conclusions: The pharmacokinetics of IDA and its main metabolite idarubicinol in CHOP-derived protocols were not different from data obtained with other combinations or monotherapy. The increased myelotoxicity of IDA may be a consequence of P-gp expression in CD34-positive HSC. Springer-Verlag, 2003 Idarubicin myelotoxicity nationallicence Pharmacokinetics nationallicence P-glycoprotein nationallicence Hematopoietic stem cells nationallicence Kroschinsky Frank 1st Medical Department, Carl Gustav Carus University Hospital, Fetscherstrasse 74, 01307, Dresden, Germany aut Schleyer Eberhard 1st Medical Department, Carl Gustav Carus University Hospital, Fetscherstrasse 74, 01307, Dresden, Germany aut Renner Ulf 1st Medical Department, Carl Gustav Carus University Hospital, Fetscherstrasse 74, 01307, Dresden, Germany aut Schimming Claudia 1st Medical Department, Carl Gustav Carus University Hospital, Fetscherstrasse 74, 01307, Dresden, Germany aut Schimmelpfennig Christoph 1st Medical Department, Carl Gustav Carus University Hospital, Fetscherstrasse 74, 01307, Dresden, Germany aut Bornhäuser Martin 1st Medical Department, Carl Gustav Carus University Hospital, Fetscherstrasse 74, 01307, Dresden, Germany aut Illmer Thomas 1st Medical Department, Carl Gustav Carus University Hospital, Fetscherstrasse 74, 01307, Dresden, Germany aut Trümper Lorenz Department of Hematology/Oncology, Georg August University, Robert-Koch-Strasse 40, 37070, Göttingen, Germany aut Ehninger Gerhard 1st Medical Department, Carl Gustav Carus University Hospital, Fetscherstrasse 74, 01307, Dresden, Germany aut Schaich Markus 1st Medical Department, Carl Gustav Carus University Hospital, Fetscherstrasse 74, 01307, Dresden, Germany aut Cancer Chemotherapy and Pharmacology Springer-Verlag 53/1(2004-01-01), 61-67 0344-5704 53:1<61 2004 53 280 https://doi.org/10.1007/s00280-003-0700-2 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00280-003-0700-2 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Kroschinsky Frank 1st Medical Department, Carl Gustav Carus University Hospital, Fetscherstrasse 74, 01307, Dresden, Germany aut NATIONALLICENCE 700 1- Schleyer Eberhard 1st Medical Department, Carl Gustav Carus University Hospital, Fetscherstrasse 74, 01307, Dresden, Germany aut NATIONALLICENCE 700 1- Renner Ulf 1st Medical Department, Carl Gustav Carus University Hospital, Fetscherstrasse 74, 01307, Dresden, Germany aut NATIONALLICENCE 700 1- Schimming Claudia 1st Medical Department, Carl Gustav Carus University Hospital, Fetscherstrasse 74, 01307, Dresden, Germany aut NATIONALLICENCE 700 1- Schimmelpfennig Christoph 1st Medical Department, Carl Gustav Carus University Hospital, Fetscherstrasse 74, 01307, Dresden, Germany aut NATIONALLICENCE 700 1- Bornhäuser Martin 1st Medical Department, Carl Gustav Carus University Hospital, Fetscherstrasse 74, 01307, Dresden, Germany aut NATIONALLICENCE 700 1- Illmer Thomas 1st Medical Department, Carl Gustav Carus University Hospital, Fetscherstrasse 74, 01307, Dresden, Germany aut NATIONALLICENCE 700 1- Trümper Lorenz Department of Hematology/Oncology, Georg August University, Robert-Koch-Strasse 40, 37070, Göttingen, Germany aut NATIONALLICENCE 700 1- Ehninger Gerhard 1st Medical Department, Carl Gustav Carus University Hospital, Fetscherstrasse 74, 01307, Dresden, Germany aut NATIONALLICENCE 700 1- Schaich Markus 1st Medical Department, Carl Gustav Carus University Hospital, Fetscherstrasse 74, 01307, Dresden, Germany aut NATIONALLICENCE 773 0- Cancer Chemotherapy and Pharmacology Springer-Verlag 53/1(2004-01-01), 61-67 0344-5704 53:1<61 2004 53 280 NATIONALLICENCE 856 40 https://doi.org/10.1007/BF02665354 text/html Onlinezugriff via DOI Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE NATIONALLICENCE NL-springer