title: Pharmacokinetic features and metabolism of calphostin C, a naturally occurring perylenequinone with antileukemic activity.
abstract: OBJECTIVE
  To examine the pharmacokinetic features and metabolism of calphostin C, a naturally occurring perylenequinone with potent antileukemic activity.
  
  
  METHODS
  HPLC-based quantitative detection methods were used to measure calphostin C levels in lysates of leukemic cells and in plasma of mice treated with calphostin C. The plasma concentration-time data were analyzed using the WinNonlin program. In vitro esterases and a microsome P450 preparation in conjunction with a LC-MS(API-EI) system were used to study the metabolism of calphostin C.
  
  
  RESULTS
  An intracellular exposure level (AUC0-6h) of 257 microM x h was achieved after in vitro treatment of NALM-6 cells with calphostin C at a 5 microM final concentration in culture medium. After intraperitoneal (i.p.) injection of a 40 mg/kg nontoxic bolus dose of calphostin C, the estimated Cmax was 2.9 microM, which is higher than the effective in vitro concentration of calphostin C against leukemic cells. Drug absorption after i.p. administration was rapid with an absorption half-life of 24.2 min and the estimated t(max) was 63.0 min. Calphostin C was cleared with an elimination half-life of 91.3 min. An inactive and smaller metabolite (calphostin B) was detected in plasma of calphostin C-treated mice with a t(max) of 41.3 min. Esterase (but not P450) treatment of calphostin C in vitro yielded an inactive metabolite (calphostin B) of the same size and elution profile.
  
  
  CONCLUSIONS
  Target plasma calphostin C concentrations of potent antileukemic activity can be reached in mice at nontoxic dose levels. This pilot pharmacokinetic study of calphostin C combined with the availability of the described quantitative HPLC method for its detection in cells and plasma provide the basis for future preclinical evaluation of calphostin C and its potential as an anti-leukemic drug.
authors.affiliation: Department of Pharmaceutical Sciences, Hughes Institute, St. Paul, Minnesota 55113, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Chen
authors.forename: H L
authors.initials: HL
authors.lastname: Tai
authors.forename: D M
authors.initials: DM
authors.lastname: Zhu
authors.forename: F M
authors.initials: FM
authors.lastname: Uckun
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D005260:Female; D006801:Humans; D051379:Mice; D009281:Naphthalenes / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000494:pharmacology; D010865:Pilot Projects; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism; D012680:Sensitivity and Specificity; D014407:Tumor Cells, Cultured
chemical_list: D000903:Antibiotics, Antineoplastic; D009281:Naphthalenes; C058819:calphostin C