title: Inverse relationship between leukaemic cell burden and plasma concentrations of daunorubicin in patients with acute myeloid leukaemia.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.affiliation: Departments of Medicine, Divisions of Clinical Pharmacology, Karolinska Institute/Karolinska University Hospital, Solna S-171 76, Stockholm, Sweden.
authors.forename: Alex
authors.initials: A
authors.lastname: Bogason
authors.forename: Angelica L
authors.initials: AL
authors.lastname: Quartino
authors.forename: Pierre
authors.initials: P
authors.lastname: Lafolie
authors.forename: Michèle
authors.initials: M
authors.lastname: Masquelier
authors.forename: Mats O
authors.initials: MO
authors.lastname: Karlsson
authors.forename: Christer
authors.initials: C
authors.lastname: Paul
authors.forename: Astrid
authors.initials: A
authors.lastname: Gruber
authors.forename: Sigurd
authors.initials: S
authors.lastname: Vitols
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018943:Anthracyclines / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D003630:Daunorubicin / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008962:Models, Theoretical; D012044:Regression Analysis
chemical_list: D018943:Anthracyclines; D003630:Daunorubicin