title: Pharmacokinetic modeling to assess factors affecting the oral bioavailability of the lactone and carboxylate forms of the lipophilic camptothecin analogue AR-67 in rats.
abstract: OBJECTIVE
  Camptothecin analogues are anticancer drugs effective when dosed in protracted schedules. Such treatment is best suited for oral formulations. AR-67 is a novel lipophilic analogue with potent efficacy in preclinical models. Here we assessed factors that may influence its oral bioavailability in rats.
  
  
  METHODS
  Plasma pharmacokinetic (PK) studies were conducted following administration of AR-67 lactone or carboxylate doses alone or after pre-dosing with inhibitors of the efflux transporters P-gp and Bcrp. A population PK model that simultaneously fitted to oral and intravenous data was used to estimate the bioavailability (F) and clearance of AR-67.
  
  
  RESULTS
  An inverse Gaussian function was used as the oral input into the model and provided the best fits. Covariate analysis showed that the bioavailability of the lactone, but not its clearance, was dose dependent. Consistent with this observation, the bioavailability of AR-67 increased when animals were pretreated orally with GF120918 or Zosuquidar.
  
  
  CONCLUSIONS
  Absorption of AR-67 is likely affected by solubility of its lactone form and interaction with efflux pumps in the gut. AR-67 appears to be absorbed as the lactone form, most likely due to gastric pH favoring its formation and predominance. F increased at higher doses suggesting saturation of efflux mechanisms.
authors: Department of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky 40536, USA.
authors: Eyob D
authors: ED
authors: Adane
authors: Zhiwei
authors: Z
authors: Liu
authors: Tian-Xiang
authors: TX
authors: Xiang
authors: Bradley D
authors: BD
authors: Anderson
authors: Markos
authors: M
authors: Leggas
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors; D000166:Acridines / Q000008:administration & dosage / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000097:blood* / Q000737:chemistry*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood*; D002264:Carboxylic Acids / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry; D005260:Female; D007783:Lactones / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage / Q000494:pharmacology; D059004:Topoisomerase I Inhibitors / Q000008:administration & dosage / Q000097:blood* / Q000737:chemistry*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C489249:Abcg2 protein, rat; D000166:Acridines; D000972:Antineoplastic Agents, Phytogenic; D002264:Carboxylic Acids; D007783:Lactones; D044005:Tetrahydroisoquinolines; D059004:Topoisomerase I Inhibitors; C083501:Elacridar; D002166:Camptothecin