Daunorubicin pharmacokinetics and the correlation with P-glycoprotein and response in patients with acute leukaemia.
The aim of this study was to examine the relationship between the pharmacokinetics of daunorubicin (DNR), overexpression of P-glycoprotein (Pgp) and treatment response in acute leukaemia. Twenty-seven patients with acute leukaemia received DNR as part of induction therapy. The plasma and cellular levels of DNR and its metabolite daunorubicinol (DOL) were determined using high-performance liquid chromatography. There were no significant differences between patients who went into complete remission (12/23) compared with those who did not respond for the following pharmacokinetic parameters: DNR and DOL plasma AUC (area under the curve) and DNR plasma half-life and clearance. There was a significant difference in the cellular DNR and DOL AUC between responders and non-responders (P < 0.02). Seven patients were Pgp positive and 18 Pgp negative. There was no correlation between patient response and the presence of Pgp (P > 0.1), nor was there any correlation between the cellular concentration of DNR or DOL and Pgp (P > 0.3). To our knowledge this is the first report examining the relationship between DNR pharmacokinetics, patient response and Pgp expression. Our data indicated that acute leukaemia patients responding to chemotherapy had higher cellular DNR and DOL than non-responders; also, overexpression of Pgp appeared not to be the sole explanation for the lower cellular DNR levels as expected from in vitro studies.
Galettis
P
P
Department of Haematology, Royal North Shore Hospital, St Leonards, New South Wales, Australia.
Boutagy
J
J
Ma
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D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D002352:Carrier Proteins / Q000378:metabolism*; D003630:Daunorubicin / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007951:Leukemia, Myeloid / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D012074:Remission Induction
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; C000847:daunorubicinol; D003630:Daunorubicin