title: Preclinical pharmacology of 2-methoxyantimycin A compounds as novel antitumor agents.
abstract: OBJECTIVE
  The present study was designed to determine pharmacological and biochemical properties of 2-methoxyantimycin A analogs (OMe-A1, OMe-A2, OMe-A3, and OMe-A5), which are novel antitumor compounds, and provide a basis for future pharmaceutical development, preclinical evaluation, and clinical trials.
  
  
  METHODS
  A high-performance liquid chromatography (HPLC) method was established and employed to assess the biostability of these analogs and to determine their pharmacokinetic properties in mice and rats.
  
  
  RESULTS
  In vitro biostability of the 2-methoxyantimycin analogs was esterase-dependent, compound-dependent, and species-dependent. In the absence of esterase inhibitors, all of the analogs were relatively unstable. Stability was greater, however, in human and dog plasma than in rat and mouse plasma. In the presence of esterase inhibitors, OMe-A1 was stable at 37 degrees C for 60 min in mouse and rat plasma, moderately stable in human plasma, and unstable in dog plasma. OMe-A2 was generally stable in all types of plasma. OMe-A3 was stable in dog and rat plasma, but not in human or mouse plasma. OMe-A5 was stable in human and dog plasma, but not in mouse or rat plasma. Each of these analogs was highly bound to plasma proteins. Of S9 fractions from four species, human S9 was least efficient in metabolizing OMe-A3. Following an intravenous dose of OMe-A1 in mice, plasma levels decreased rapidly, with an initial half-life of 2.7 min and a terminal half life of 34 min. Following an intraperitoneal dose in mice, plasma levels decreased less rapidly with a terminal half-life of 215 min. Following an intravenous dose of OMe-A1 or OMe-A3 in rats, plasma levels decreased more rapidly with initial half-lives of about 1.0 min. At an equivalent dose, OMe-A3 had a faster clearance than OMe-A1.
  
  
  CONCLUSIONS
  For 2-methoxyantimycin A analogs, species differences in biostability, metabolism, and pharmacokinetics may be pertinent in assessing their pharmacological and toxicological profiles and antitumor activity in humans.
authors.affiliation: Department of Pharmacology and Toxicology, Division of Clinical Pharmacology, Cancer Pharmacology Laboratory, Comprehensive Cancer Center, University of Alabama, Birmingham, AL, 35294, USA. hui.wang@ccc.uab.edu
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Mao
authors.initials: M
authors.lastname: Li
authors.forename: Julie K
authors.initials: JK
authors.lastname: Rhie
authors.forename: David M
authors.initials: DM
authors.lastname: Hockenbery
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Covey
authors.forename: Ruiwen
authors.initials: R
authors.lastname: Zhang
authors.forename: Donald L
authors.initials: DL
authors.lastname: Hill
mesh_terms: D000818:Animals; D000968:Antimycin A / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D011916:Rats, Inbred F344; D013045:Species Specificity
chemical_list: D000970:Antineoplastic Agents; D000968:Antimycin A