title: Involvement of P-glycoprotein, multidrug resistance protein 2 and breast cancer resistance protein in the transport of belotecan and topotecan in Caco-2 and MDCKII cells.
abstract: OBJECTIVE
  To investigate the underlying mechanism of low bioavailabilities of the water-soluble camptothecin derivatives, belotecan and topotecan.
  
  
  METHODS
  The bioavailability of belotecan and topotecan in rats was determined following oral administration of each drug at a dose of 5 mg/kg body weight. The vectorial transport of each drug was measured in Caco-2 and engineered MDCK II cells.
  
  
  RESULTS
  The bioavailability of belotecan (11.4%) and topotecan (32.0%) in rats was increased to 61.5% and 40.8%, respectively, by the preadministration of CsA at a dose of 40 mg/kg. Contrary to the absorptive transport, the secretory transport of these drugs across the Caco-2 cell monolayer was concentration-dependent, saturable, and significantly inhibited by the cis presence of verapamil (a P-gp substrate), MK-571 (an MRP inhibitor), bromosulfophthalein (BSP, an MRP2 inhibitor), fumitremorgin C (FTC, a BCRP inhibitor) and cyclosporine A (CsA, an inhibitor of P-gp and BCRP, and a substrate of P-gp) suggesting the involvement of these transporters, which could be further confirmed in MDCKII/P-gp, MDCKII/MRP2 and MDCKII/BCRP cells.
  
  
  CONCLUSIONS
  The involvement of secretory transporters P-gp, MRP2 and BCRP, particularly for belotecan, as well as a low passive permeability, appears to be responsible for the low bioavailability of belotecan and topotecan.
authors.affiliation: National Research Laboratory for Transporters Targeted Drug Design, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, 599 Gwanangno, Gwanak-gu, Seoul 151-742, Republic of Korea.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: Hyo-Eon
authors.initials: HE
authors.lastname: Jin
authors.forename: Wooyoung
authors.initials: W
authors.lastname: Kim
authors.forename: Yong-Hae
authors.initials: YH
authors.lastname: Han
authors.forename: Dae-Duk
authors.initials: DD
authors.lastname: Kim
authors.forename: Suk-Jae
authors.initials: SJ
authors.lastname: Chung
authors.forename: Chang-Koo
authors.initials: CK
authors.lastname: Shim
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001692:Biological Transport; D018938:Caco-2 Cells; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004285:Dogs; D006801:Humans; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000502:physiology*; D009363:Neoplasm Proteins / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019772:Topotecan / Q000493:pharmacokinetics*
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; D000970:Antineoplastic Agents; D002166:Camptothecin; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D019772:Topotecan; C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human; C489249:Abcg2 protein, rat; C116963:belotecan