title: The elimination of MTC-220, a novel anti-tumor agent of conjugate of paclitaxel and muramyl dipeptide analogue, in rats.
abstract: OBJECTIVE
  MTC-220, a conjugate of paclitaxel and muramyl dipeptide analogue, was reported to exhibit anti-tumor ability and anti-metastatic effect. The aim of present study was to investigate the elimination of MTC-220 and the related mechanisms in rats.
  
  
  METHODS
  The excretion of MTC-220 and its metabolites in bile and urine were determined in rats after intravenous administration at 4 mg/kg. Caco-2 cell monolayer, in situ liver perfusion model and in vivo pharmacokinetics with selected inhibitors in rats were used to confirm the involvement of hepatic transporters in the elimination of MTC-220. The metabolic stability of MTC-220 was assessed by the incubation with rat liver microsomes and plasma.
  
  
  RESULTS
  Approximately 72 % of MTC-220 was excreted into bile and less than 0.02 % into urine after administration in rats. The Caco-2 cell monolayer was impermeable to MTC-220. In in situ liver perfusion model, the hepatic extraction ratio of MTC-220 was reduced to 40 % of control in the presence of rifampicin, an Oatps inhibitor, and the cumulative biliary excretion rates of MTC-220 were reduced to 52.9, 71.5 and 62.9 % of control when concomitant perfusion with probenecid, novobiocin and verapamil, the inhibitors of Mrp2, Bcrp and P-gp, respectively. Co-administration of rifampicin, probenecid, novobiocin and verapamil with MTC-220 increased the AUC0-t and decreased the CL of MTC-220 in certain extents in rats. MTC-220 remained metabolically intact in rat liver microsomes, but less stable in plasma incubation.
  
  
  CONCLUSIONS
  In summary, the elimination of MTC-220 was mainly through the biliary excretion in unchanged form in rats. Liver transporters including Oatps, Mrp2, Bcrp and P-gp might be all involved in the hepatic elimination of MTC-220. MTC-220 exhibited the high metabolic stability in liver microsomes, but less stable in plasma. The esterases might involve in the metabolism of MTC-220 in plasma.
authors.affiliation: Department of Drug Metabolism, Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing City 100050, China.
authors.forename: Feng
authors.initials: F
authors.lastname: You
authors.forename: Jinping
authors.initials: J
authors.lastname: Hu
authors.forename: Xue
authors.initials: X
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D001646:Bile / Q000737:chemistry; D001692:Biological Transport; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects; D004151:Dipeptides / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D004347:Drug Interactions; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000378:metabolism; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000970:Antineoplastic Agents; D004151:Dipeptides; C582620:MTC-220; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D017239:Paclitaxel