Substrate- and species-dependent inhibition of P-glycoprotein-mediated transport: implications for predicting in vivo drug interactions

J Pharm Sci. 2011 Aug;100(8):3055-3061. doi: 10.1002/jps.22566. Epub 2011 Apr 11.


P-glycoprotein (P-gp)-based drug interactions are a major concern in the clinic and in preclinical drug development, especially with respect to the intestinal absorption of drugs and distribution of drugs across the blood-brain barrier. Thus, there is significant interest in developing in vitro (e.g., cell culture) and in vivo models (e.g., rodents) to predict such interactions. In order to generate accurate predictions from these models, however, an understanding of the magnitude of substrate- and species-dependent differences in P-gp inhibition is required. We have used a sensitive flow cytometry assay to measure the ability of various drugs to inhibit the initial rate of accumulation of two fluorescent drug analogs (probe substrates), 4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s -indacene (BODIPY)-verapamil and BODIPY-prazosin, into Lewis lung carcinoma-porcine kidney 1 (LLC-PK1) cells expressing human or rat P-gp. The inhibition of P-gp-mediated efflux of these two fluorescent substrates by several drugs, including quinidine and itraconazole, was found to be substrate- and/or species-dependent. These data suggest that to provide accurate prediction of clinically significant P-gp drug interactions, multiple P-gp substrates will need to be used in both in vitro and in vivo (including human) drug interaction studies. In addition, extrapolation of P-gp-based drug interaction in rodents to humans must be conducted with caution.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / antagonists & inhibitors*
  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • Animals
  • Biological Transport
  • Boron Compounds / chemistry
  • Boron Compounds / pharmacokinetics
  • Drug Evaluation, Preclinical
  • Drug Interactions
  • Flow Cytometry
  • Fluorescent Dyes / chemistry
  • Fluorescent Dyes / pharmacokinetics
  • Humans
  • Pharmaceutical Preparations / chemistry
  • Pharmaceutical Preparations / metabolism
  • Prazosin / chemistry
  • Prazosin / pharmacokinetics*
  • Rats
  • Species Specificity
  • Substrate Specificity
  • Swine
  • Verapamil / chemistry
  • Verapamil / pharmacokinetics*


  • 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene
  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Boron Compounds
  • Fluorescent Dyes
  • Pharmaceutical Preparations
  • multidrug resistance protein 3
  • Verapamil
  • Prazosin