title: Organic anion transporting polypeptide 2-mediated uptake of paclitaxel and 2'-ethylcarbonate-linked paclitaxel in freshly isolated rat hepatocytes.
abstract: OBJECTIVE
  The P-glycoprotein (P-gp) efflux pump plays an important role in paclitaxel detoxification. However, hepatic uptake of paclitaxel mediated by a solute-linked carrier transporter family is still poorly understood in animals and humans. Freshly isolated hepatocyte suspensions are a well established in-vitro model for studying drug transport and xenobiotic metabolism. Therefore, the hepatic uptake of paclitaxel and its P-gp-insensitive prodrug, 2'-ethylcarbonate-linked paclitaxel (TAX-2'-Et), has been characterized using freshly isolated and pregnenolone-16-alpha-carbonitrile (PCN)-treated hepatocytes in rats.
  
  
  METHODS
  Paclitaxel and TAX-2'-Et were incubated with rat hepatocyte suspensions in the presence or absence of inhibitors.
  
  
  RESULTS
  Paclitaxel and TAX-2'-Et showed concentration-dependent uptake in rat hepatocytes. The intrinsic transport capacity was two-fold higher for paclitaxel uptake than for TAX-2'-Et uptake. Rifampicin (a potent inhibitor of organic anion transporting polypeptide (Oatp) 2), but not indometacin (a representative inhibitor of organic anion transporter (Oat) 2 and Oatp1) treatment, significantly inhibited the uptake of paclitaxel and TAX-2'-Et. We characterized the rifampicin-sensitive uptake of paclitaxel and TAX-2'-Et using rat hepatocytes treated with PCN, which dramatically enhances hepatic Oatp2 protein levels. PCN-treated hepatocytes displayed a 1.6-fold greater uptake of paclitaxel and TAX-2'-Et than the vehicle-treated hepatocytes. The uptake of the two compounds was significantly reduced by rifampicin but not by indometacin treatment. These findings demonstrated that the rat Oatp2, but not Oatp1 or Oat2, was a candidate transporter for the hepatic uptake of paclitaxel and TAX-2'-Et.
  
  
  CONCLUSIONS
  The findings have provided an important step towards identifying a key transporter in hepatic detoxification of paclitaxel and TAX-2'-Et in small animals.
authors.affiliation: School of Pharmacy, Kinki University, Higashi-Osaka, Osaka, Japan. tanino@phar.kindai.ac.jp
authors.forename: Tadatoshi
authors.initials: T
authors.lastname: Tanino
authors.forename: Akihiro
authors.initials: A
authors.lastname: Nawa
authors.forename: Mao
authors.initials: M
authors.lastname: Nakao
authors.forename: Manabu
authors.initials: M
authors.lastname: Noda
authors.forename: Sawako
authors.initials: S
authors.lastname: Fujiwara
authors.forename: Masahiro
authors.initials: M
authors.lastname: Iwaki
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000378:metabolism*; D008297:Male; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D017239:Paclitaxel / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology; D011355:Prodrugs; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D029362:Organic Anion Transporters, Sodium-Independent; D027701:Organic Cation Transport Proteins; D011355:Prodrugs; C088800:Slc22a7 protein, rat; C421102:Slco1a1 protein, rat; C451262:Slco1c1 protein, rat; C533210:paclitaxel 2'-ethylcarbonate; D011285:Pregnenolone Carbonitrile; D017239:Paclitaxel