AIMS: It has been shown that the cellular uptake and cytotoxicity of anthracyclines decrease with increasing cell density in vitro, an event termed 'the inocculum effect'. It is not known whether such an effect occurs in vivo. In this study the relationships between white blood cell (WBC) count, plasma and cellular concentrations of daunorubicin (DNR) in patients with acute myeloid leukaemia were investigated. METHODS: Plasma and mononuclear blood cells were isolated from peripheral blood from 40 patients with acute myeloid leukaemia at end of infusion (time 1 h), 5 and 24 h following the first DNR infusion. DNR concentrations were determined by high-pressure liquid chromatography and related to the WBC count at diagnosis. A population pharmacokinetic model was used to estimate the correlations between baseline WBC count, volume of distribution and clearance of DNR. RESULTS: A clear but weak inverse relationship between the baseline WBC count and plasma concentrations of DNR (r(2)=0.11, P<0.05) at time 1 was found. Furthermore, a clear relationship between baseline WBC count and DNR central volume of distribution using population pharmacokinetic modelling (dOFV 4.77, P<0.05) was also noted. Analysis of plasma DNR and the metabolite daunorubicinol (DOL) concentrations in patients with a high WBC count support that the low DNR/DOL concentrations are due a distribution effect. CONCLUSION: This study shows that the leukaemic cell burden influences the plasma concentrations of anthracyclines. Further studies are needed to explore if patients with high a WBC count may require higher doses of anthracyclines.
AIMS: It has been shown that the cellular uptake and cytotoxicity of anthracyclines decrease with increasing cell density in vitro, an event termed 'the inocculum effect'. It is not known whether such an effect occurs in vivo. In this study the relationships between white blood cell (WBC) count, plasma and cellular concentrations of daunorubicin (DNR) in patients with acute myeloid leukaemia were investigated. METHODS: Plasma and mononuclear blood cells were isolated from peripheral blood from 40 patients with acute myeloid leukaemia at end of infusion (time 1 h), 5 and 24 h following the first DNR infusion. DNR concentrations were determined by high-pressure liquid chromatography and related to the WBC count at diagnosis. A population pharmacokinetic model was used to estimate the correlations between baseline WBC count, volume of distribution and clearance of DNR. RESULTS: A clear but weak inverse relationship between the baseline WBC count and plasma concentrations of DNR (r(2)=0.11, P<0.05) at time 1 was found. Furthermore, a clear relationship between baseline WBC count and DNR central volume of distribution using population pharmacokinetic modelling (dOFV 4.77, P<0.05) was also noted. Analysis of plasma DNR and the metabolite daunorubicinol (DOL) concentrations in patients with a high WBC count support that the low DNR/DOL concentrations are due a distribution effect. CONCLUSION: This study shows that the leukaemic cell burden influences the plasma concentrations of anthracyclines. Further studies are needed to explore if patients with high a WBC count may require higher doses of anthracyclines.
Authors: U Tidefelt; J Liliemark; A Gruber; E Liliemark; B Sundman-Engberg; G Juliusson; L Stenke; A Elmhorn-Rosenborg; L Möllgård; S Lehman; D Xu; A Covelli; B Gustavsson; C Paul Journal: J Clin Oncol Date: 2000-05 Impact factor: 44.544
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Authors: N Boissel; J M Cayuela; C Preudhomme; X Thomas; N Grardel; X Fund; I Tigaud; E Raffoux; P Rousselot; F Sigaux; L Degos; S Castaigne; P Fenaux; H Dombret Journal: Leukemia Date: 2002-09 Impact factor: 11.528
Authors: Sophie Callies; Dinesh P de Alwis; Atul Mehta; Michael Burgess; Leon Aarons Journal: Cancer Chemother Pharmacol Date: 2004-03-24 Impact factor: 3.333
Authors: Sophie M Stief; Anna-Li Hanneforth; Sabrina Weser; Raphael Mattes; Michela Carlet; Wen-Hsin Liu; Michael D Bartoschek; Helena Domínguez Moreno; Matthias Oettle; Julia Kempf; Binje Vick; Bianka Ksienzyk; Belay Tizazu; Maja Rothenberg-Thurley; Hilmar Quentmeier; Wolfgang Hiddemann; Sebastian Vosberg; Philipp A Greif; Klaus H Metzeler; Gunnar Schotta; Sebastian Bultmann; Irmela Jeremias; Heinrich Leonhardt; Karsten Spiekermann Journal: Leukemia Date: 2019-06-14 Impact factor: 11.528