Organic anion transporting polypeptide 2-mediated uptake of paclitaxel and 2'-ethylcarbonate-linked paclitaxel in freshly isolated rat hepatocytes

J Pharm Pharmacol. 2009 Aug;61(8):1029-35. doi: 10.1211/jpp/61.08.0006.

Abstract

Objectives: 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.

Key findings: 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.

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / administration & dosage
  • Antineoplastic Agents, Phytogenic / pharmacokinetics*
  • Dose-Response Relationship, Drug
  • Hepatocytes / metabolism*
  • Male
  • Organic Anion Transporters, Sodium-Independent / metabolism
  • Organic Cation Transport Proteins / metabolism*
  • Paclitaxel / administration & dosage
  • Paclitaxel / analogs & derivatives*
  • Paclitaxel / pharmacokinetics
  • Pregnenolone Carbonitrile / pharmacology
  • Prodrugs
  • Rats
  • Rats, Wistar

Substances

  • Antineoplastic Agents, Phytogenic
  • Organic Anion Transporters, Sodium-Independent
  • Organic Cation Transport Proteins
  • Prodrugs
  • Slc22a7 protein, rat
  • Slco1a1 protein, rat
  • Slco1c1 protein, rat
  • paclitaxel 2'-ethylcarbonate
  • Pregnenolone Carbonitrile
  • Paclitaxel