Involvement of Mrp2/MRP2 in the species different excretion route of benzylpenicillin between rat and human

Xenobiotica. 2009 Feb;39(2):171-81. doi: 10.1080/00498250802642256.


1. The purpose of this study was to investigate the involvement of rat Mrp2 and human MRP2 in benzylpenicillin transport using canalicular liver plasma membrane (cLPM) vesicles isolated from Sprague-Dawley or Easai hyperbilirubinemic (EHBR) rats, and MDCKII cells overexpressing MRP2. 2. The adenosine triphosphate (ATP)-dependent uptake of benzylpenicillin and oestradiol-17beta-D-glucuronide (E(2)17betaG), a representative substrate for Mrp2, into EHBR-cLPM vesicles was decreased relative to that seen with control-cLPM vesicles, which may reflect the absence of Mrp2 in the EHBR. The ATP-dependent uptake of taurocholate, which is not a substrate for Mrp2, was similar in both control and EHBR-cLPM vesicles. The concentration dependence of ATP-dependent benzylpenicillin uptake was reflected in a K(m) of 44.0 microM and a V(max) of 508.4 pmol mg(-1) min(-1). Additional inhibition studies using E(2)17betaG and methotrexate as representative substrates for Mrp2/MRP2 demonstrated the involvement of rat Mrp2, but not human MRP2, in benzylpenicillin efflux. Benzylpenicillin appears not to be a substrate for or inhibitor of other human efflux transporters such as MDR1, MRP1, MRP3, or BCRP. 3. In conclusion, rat Mrp2, but not human MRP2, plays an important role in ATP-dependent benzylpenicillin uptake in the bile canalicular membrane, which may explain why biliary excretion of benzylpenicillin is high in the rat but negligible in humans.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / physiology*
  • Adenosine Triphosphate / metabolism
  • Animals
  • Anti-Bacterial Agents / pharmacokinetics*
  • Biological Transport
  • Cell Line
  • Cyclosporine / pharmacology
  • Dogs
  • Estradiol / analogs & derivatives
  • Estradiol / pharmacokinetics
  • Flow Cytometry
  • Humans
  • Male
  • Multidrug Resistance-Associated Protein 2
  • Multidrug Resistance-Associated Proteins / physiology*
  • Penicillin G / pharmacokinetics*
  • Rats
  • Rats, Inbred Strains
  • Rats, Sprague-Dawley
  • Rhodamines / metabolism
  • Species Specificity
  • Substrate Specificity
  • Taurocholic Acid / pharmacokinetics
  • Transport Vesicles / metabolism
  • p-Aminohippuric Acid / pharmacology


  • ABCC2 protein, human
  • ATP-Binding Cassette Transporters
  • Abcc2 protein, rat
  • Anti-Bacterial Agents
  • Multidrug Resistance-Associated Protein 2
  • Multidrug Resistance-Associated Proteins
  • Rhodamines
  • estradiol-17 beta-glucuronide
  • Estradiol
  • Taurocholic Acid
  • Cyclosporine
  • Adenosine Triphosphate
  • Penicillin G
  • p-Aminohippuric Acid