title: P-Glycoprotein inhibitor valspodar (PSC 833) increases the intracellular concentrations of daunorubicin in vivo in patients with P-glycoprotein-positive acute myeloid leukemia.
abstract: OBJECTIVE
  The aim of the present study was to evaluate the effect of the cyclosporine derivative valspodar (PSC 833; Amdray, Novartis Pharma, Basel, Switzerland) on the concentration of daunorubicin (dnr) in leukemic blast cells in vivo during treatment.
  
  
  METHODS
  Ten patients with acute myeloid leukemia (AML) were included. Leukemic cells from seven of the patients were P-glycoprotein (Pgp)-positive. dnr 100 mg/m(2) was given as a continuous infusion over 72 hours. After 24 hours, a loading dose of valspodar was given, followed by a 36-hour infusion of 10 mg/kg per 24 hours. Blood samples were drawn at regular intervals, and concentrations of dnr and its main metabolite, daunorubicinol, in plasma and isolated leukemic cells were determined by high-pressure liquid chromatography.
  
  
  RESULTS
  The mean dnr concentrations in leukemic cells 24 hours after the start of infusion (before valspodar) were 18.8 micromol/L in Pgp-negative samples and 13.5 micromol/L in Pgp-positive samples. After 8 hours of valspodar infusion, these values were 25.8 and 24.0 micromol/L, respectively. The effect of valspodar was evaluated from the ratio of the area under the curve (AUC) for dnr concentration versus time in leukemic cells to the AUC for dnr concentration against time in the plasma. For the seven patients with Pgp-positive leukemia, the mean ratio increased by 52%, from 545 on day 1 to 830 on day 2 (P<.05) when valspodar was given. In the three patients with Pgp-negative leukemia, no significant difference was observed.
  
  
  CONCLUSIONS
  These results strongly suggest that valspodar, by interacting with Pgp, can increase the cellular uptake of dnr in leukemic blasts in vivo.
authors.affiliation: Department of Hematology, Orebro Medical Center Hospital, Orebro, Sweden. ulf.tidefelt@orebroll.se
authors.forename: U
authors.initials: U
authors.lastname: Tidefelt
authors.forename: J
authors.initials: J
authors.lastname: Liliemark
authors.forename: A
authors.initials: A
authors.lastname: Gruber
authors.forename: E
authors.initials: E
authors.lastname: Liliemark
authors.forename: B
authors.initials: B
authors.lastname: Sundman-Engberg
authors.forename: G
authors.initials: G
authors.lastname: Juliusson
authors.forename: L
authors.initials: L
authors.lastname: Stenke
authors.forename: A
authors.initials: A
authors.lastname: Elmhorn-Rosenborg
authors.forename: L
authors.initials: L
authors.lastname: Möllgård
authors.forename: S
authors.initials: S
authors.lastname: Lehman
authors.forename: D
authors.initials: D
authors.lastname: Xu
authors.forename: A
authors.initials: A
authors.lastname: Covelli
authors.forename: B
authors.initials: B
authors.lastname: Gustavsson
authors.forename: C
authors.initials: C
authors.lastname: Paul
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics*; D003524:Cyclosporins / Q000494:pharmacology*; D003630:Daunorubicin / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D003524:Cyclosporins; C070272:valspodar; D003630:Daunorubicin