title: Preclinical pharmacology of the novel antitumor agent adaphostin, a tyrphostin analog that inhibits bcr/abl.
abstract: OBJECTIVE
  To define several pharmacological properties for the potential anticancer agent, adaphostin, in order to determine whether the compound is appropriate for clinical evaluation as an anticancer agent.
  
  
  METHODS
  The analytical procedure involved high-performance liquid chromatography and utilized an analytical J'Sphere ODS H-80 column.
  
  
  RESULTS
  The stability of adaphostin at two different concentrations was determined at temperatures of 37 degrees C, 4 degrees C, and -80 degrees C, in the plasma of mice, rats, dogs, and humans. The compound was most stable at the lower temperatures. At all temperatures, adaphostin was generally most stable in human plasma and least stable in dog plasma. Adaphostin bound strongly (>93%) to proteins in plasma from all four species. Following intravenous (i.v.) administration to mice (50 mg/kg; 150 mg/m(2)), plasma concentrations declined rapidly from 50 microM at 2 min to 1 microM at 2 h. Elimination was triexponential, with t (1/2) values of 1.1, 9.1, and 41.2 min. The Cl(tb) was 0.411 L/(min.m(2)), the V (dss) was 24.6 L/m(2), and the AUC was 927 microM.min. In a comparison of vehicles for intraperitoneal (i.p.) dosing, PEG 300 allowed the highest plasma concentrations of adaphostin. Bioavailability following an i.p. dose was greater than that following a subcutaneous dose, or that for a dose administered by oral gavage. For rats dosed i.v. with adaphostin (50 mg/kg; 300 mg/m(2)), plasma concentrations also decreased triexponentially, with t (1/2) values of 1.8, 10.6, and 136 min. Other pharmacokinetic values were Cl(tb) = 0.466 L/(min.m(2)), AUC = 1,161 microM.min, and V (dss)=8.0 L/m(2). Analysis of samples collected from two dogs dosed i.v. with adaphostin (7.5 mg/kg; 150 mg/m(2)) showed that plasma concentrations decreased in a biphasic manner, with individual values for t (1/2alpha) of 6.0 and 9.8 min for the distribution phase and t (1/2beta) of 40.6 and 66.2 min for the elimination phase. Other pharmacokinetic values were Cl(tb) = 0.565 and 0.852 L/(min.m(2)), AUC = 673 and 446 microM min, and V (dss) = 29.6 and 56.8 L/m(2).
  
  
  CONCLUSIONS
  The stability of adaphostin in plasma varies with species. In mice and dogs dosed with adaphostin, plasma concentrations of the compound decreased rapidly. The clearance of adaphostin from plasma, on an m(2) basis, was equivalent for mice and rats but more rapid in dogs. These results are relevant for assessing the pharmacologic and toxicologic profiles and the antitumor activity of adaphostin in humans.
authors.affiliation: Department of Pharmacology and Toxicology, Division of Clinical Pharmacology, Cancer Pharmacology Laboratory, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
authors.forename: Mao
authors.initials: M
authors.lastname: Li
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Donald L
authors.initials: DL
authors.lastname: Hill
authors.forename: Sherman
authors.initials: S
authors.lastname: Stinson
authors.forename: Karen
authors.initials: K
authors.lastname: Veley
authors.forename: Irma
authors.initials: I
authors.lastname: Grossi
authors.forename: James
authors.initials: J
authors.lastname: Peggins
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Covey
authors.forename: Ruiwen
authors.initials: R
authors.lastname: Zhang
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001798:Blood Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D006801:Humans; D006873:Hydroquinones / Q000493:pharmacokinetics / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008657:Metabolic Clearance Rate; D051379:Mice; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors*; D051562:Proto-Oncogene Proteins c-bcr / Q000037:antagonists & inhibitors*; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D000970:Antineoplastic Agents; D001798:Blood Proteins; D006873:Hydroquinones; C404397:NSC 680410; D016315:Proto-Oncogene Proteins c-abl; D051562:Proto-Oncogene Proteins c-bcr; D000218:Adamantane