title: Alpha1 acid glycoprotein binds to imatinib (STI571) and substantially alters its pharmacokinetics in chronic myeloid leukemia patients.
abstract: OBJECTIVE
  Imatinib (Glivec) is a potent inhibitor of bcr/abl, an oncogenic fusion protein that causes chronic myelogenous leukemia (CML). alpha1 acid glycoprotein (AGP) binds to imatinib with high affinity and inhibits imatinib activity in vitro and in vivo in an animal model. A pharmacokinetics analysis of imatinib was undertaken in CML patients.
  
  
  METHODS
  Imatinib plasma concentrations were measured in 19 CML patients treated with imatinib (400 or 600 mg/day). Five patients received a concomitant short-term course of clindamycin (CLI).
  
  
  RESULTS
  A positive correlation between AGP and imatinib plasma levels was observed. CLI administration decreased imatinib plasma concentrations, evaluated as area under the curve (AUC) and peak concentrations (C(max)). The effects of a bolus of CLI was studied in three patients on imatinib 23 h after the last imatinib dose. Within 5-10 min in three of three cases, CLI caused a decrease in imatinib plasma concentrations of 2.6-, 2.7-, and 4.7-fold, respectively. In vitro experiments using fresh blasts from CML patients showed that AGP, at concentrations observed in the patients, decreased imatinib intracellular concentrations up to 10 times and blocked imatinib activity. The incubation with CLI restored imatinib intracellular concentrations and biological activity.
  
  
  CONCLUSIONS
  AGP exerts significant effects of the pharmacokinetics, plasma concentrations, and intracellular distribution of imatinib in CML patients; these data indicate that plasma imatinib levels represent unreliable indicators of the cellular concentrations of this molecule.
authors.affiliation: Department of Experimental Oncology, Istituto Nazionale Tumori, Milano, Italy. carlo.gambacorti@istitutotumori@mi.it
authors.forename: Carlo
authors.initials: C
authors.lastname: Gambacorti-Passerini
authors.forename: Massimo
authors.initials: M
authors.lastname: Zucchetti
authors.forename: Domenico
authors.initials: D
authors.lastname: Russo
authors.forename: Roberta
authors.initials: R
authors.lastname: Frapolli
authors.forename: Magda
authors.initials: M
authors.lastname: Verga
authors.forename: Silvia
authors.initials: S
authors.lastname: Bungaro
authors.forename: Lucia
authors.initials: L
authors.lastname: Tornaghi
authors.forename: Fabio
authors.initials: F
authors.lastname: Rossi
authors.forename: Pietro
authors.initials: P
authors.lastname: Pioltelli
authors.forename: Enrico
authors.initials: E
authors.lastname: Pogliani
authors.forename: Daniele
authors.initials: D
authors.lastname: Alberti
authors.forename: Gianmarco
authors.initials: G
authors.lastname: Corneo
authors.forename: Maurizio
authors.initials: M
authors.lastname: D'Incalci
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D001549:Benzamides; D001752:Blast Crisis; D002455:Cell Division; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009961:Orosomucoid / Q000378:metabolism*; D010879:Piperazines / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011485:Protein Binding; D011743:Pyrimidines / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013936:Thymidine / Q000378:metabolism; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D009961:Orosomucoid; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D013936:Thymidine