title: Factors affecting the in vivo lactone stability and systemic clearance of the lipophilic camptothecin analogue AR-67.
abstract: OBJECTIVE
  The narrow efficacy-toxicity window of anticancer agents necessitates understanding of factors contributing to their disposition. This is especially true for camptothecins as they exist in the lactone and carboxylate forms with each moiety differentially interacting with efflux or uptake transporters. Here we determined the disposition of the lactone and carboxylate forms of AR-67, a 3(rd) generation camptothecin analogue.
  
  
  METHODS
  Pharmacokinetic studies were conducted in rats given intravenous boluses of AR-67 lactone or carboxylate with or without pharmacologic inhibitor pretreatment (GF120918 or rifampin). Pharmacokinetic modeling was used to estimate clearances, while simulations assessed the impact of clearance changes on overall AR-67 exposure.
  
  
  RESULTS
  Our modeling showed that carboxylate clearance was 3.5-fold higher than that of the lactone. GF120918 decreased lactone clearance only, but rifampin decreased both lactone and carboxylate clearances. Simulations showed that decreasing carboxylate clearance, which controls the overall drug disposition, leads to significant increase in AR-67 exposure.
  
  
  CONCLUSIONS
  The apparent in vivo blood stability of AR-67 is partly dependent on the increased carboxylate clearance. This may have clinical implications for populations with single nucleotide polymorphisms that impair the function of uptake transporter genes (e.g., SLCO1B1), which are potentially responsible for AR-67 carboxylate clearance.
authors.affiliation: Department of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Eyob D
authors.initials: ED
authors.lastname: Adane
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Liu
authors.forename: Tian-Xiang
authors.initials: TX
authors.lastname: Xiang
authors.forename: Bradley D
authors.initials: BD
authors.lastname: Anderson
authors.forename: Markos
authors.initials: M
authors.lastname: Leggas
mesh_terms: D000818:Animals; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D005260:Female; D007783:Lactones / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D008954:Models, Biological; D015394:Molecular Structure; D017646:Organosilicon Compounds / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D007783:Lactones; D017646:Organosilicon Compounds; C415575:7-tert-butyldimethylsilyl-10-hydroxycamptothecin; D002166:Camptothecin