Increased myelotoxicity of idarubicin: is there a pharmacological basis? Results of a pharmacokinetic and an in vitro cytotoxicity study.

摘要: 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. is known be less sensitive towards multidrug resistance mediated by P-glycoprotein (P-gp). This phenotype a major impediment successful antineoplastic treatment, but P-gp also expressed on hematopoietic stem cells (HSC).Methods: We investigated the pharmacokinetics etoposide (ETO) seven previously untreated patients with aggressive NHL. The received CHOP-derived protocol (CIVEP) which doxorubicin (DOX) was substituted 11–16 mg/m2 ETO 3×100 added. Furthermore, we evaluated vitro impact expression cytotoxicity DOX from three parental chemosensitive leukemia cell lines (HL60, U937, CCRF) their resistant sublines, as well CD34-positive HSC.Results: peak plasma levels (Cmax), terminal elimination half-life (t1/2) area under concentration curve (AUC) both did not differ published data. In line models numbers viable P-gp-expressing CCRF-VCR100 subline were significantly more reduced (P<0.001), there no difference cytotoxicities CCRF (non-P-gp-expressing) U937 HL60 sublines. Cytotoxicity against HSC pronounced after incubation than treatment (P=0.014), even when tenfold higher used. addition cyclosporin A cytotoxic effect that HSC.Conclusions: its main metabolite idarubicinol protocols different data obtained combinations or monotherapy. may consequence HSC.