title: Pharmacokinetics of 5-azacitidine administered with phenylbutyrate in patients with refractory solid tumors or hematologic malignancies.
abstract: OBJECTIVE
  To characterize the pharmacokinetic behavior of 5-azacitidine (5-AC), a cytidine nucleoside analog, when given with phenylbutyrate, a histone deaceytlase inhibitor.
  
  
  METHODS
  Pharmacokinetic data were obtained from two trials involving patients with solid tumor and hematologic malignancies. 5-AC at doses ranging from 10 to 75 mg/m2/d was administered once daily as a subcutaneous injection for 5 to 21 days in combination with phenylbutyrate administered as a continuous intravenous infusion for varying dose and duration every 28 or 35 days. Serial plasma samples were collected up to 24 hours after 5-AC administration. 5-AC was quantitated using a validated liquid chromatograph/tandem mass spectrometry method.
  
  
  RESULTS
  5-AC was rapidly absorbed with the mean T(max) occurring at 0.47 hour. Average maximum concentration (C(max)) and area under the curve (AUC(0-infinity)) values increased in a dose-proportionate manner with increasing dose from 10 to 75 mg/m2/d; the mean +/- SD C(max) and AUC(0-infinity) at 10 mg/m2/d were 776 +/- 459 nM and 1,355 +/- 1,125 h*nM, respectively, and at 75 mg/m2/d were 4,871 +/- 1,398 nM and 6,582 +/- 2,560 h*nM, respectively. Despite a short terminal half-life of 1.5 +/- 2.3 hours, inhibition of DNA methyl transferase activity in tumors of patients receiving 5-AC has been documented.
  
  
  CONCLUSIONS
  5-AC is rapidly absorbed and eliminated when administered subcutaneously. Sufficient 5-AC exposure is achieved to produce pharmacodynamic effects in tumors.
authors.affiliation: Division of Medical Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA. mrudek2@jhmi.edu
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Rudek
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: Ping
authors.initials: P
authors.lastname: He
authors.forename: Carol
authors.initials: C
authors.lastname: Hartke
authors.forename: Jill
authors.initials: J
authors.lastname: Gilbert
authors.forename: Steven D
authors.initials: SD
authors.lastname: Gore
authors.forename: Michael A
authors.initials: MA
authors.lastname: Carducci
authors.forename: Sharyn D
authors.initials: SD
authors.lastname: Baker
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001374:Azacitidine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D019337:Hematologic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D008657:Metabolic Clearance Rate; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000378:metabolism; D010654:Phenylbutyrates / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D000964:Antimetabolites, Antineoplastic; D010654:Phenylbutyrates; D001374:Azacitidine