Intestinal drug transporter expression and the impact of grapefruit juice in humans

Clin Pharmacol Ther. 2007 Mar;81(3):362-70. doi: 10.1038/sj.clpt.6100056. Epub 2007 Jan 10.


The goals of this study were to assess the extent of human intestinal drug transporter expression, determine the subcellular localization of the drug uptake transporter OATP1A2, and then to assess the effect of grapefruit juice consumption on OATP1A2 expression relative to cytochrome P450 3A4 and MDR1. Expression of drug uptake and efflux transporters was assessed using human duodenal biopsy samples. Fexofenadine uptake by different transporters was measured in a transporter-transfected cell line. We investigated the influence of grapefruit juice on pharmacokinetics of orally administered fexofenadine. The effect of grapefruit juice on the expression of intestinal transporters was determined using real-time polymerase chain reaction and Western blot analysis. In the duodenum of healthy volunteers, an array of CYP enzymes as well as uptake and efflux transporters was expressed. Importantly, uptake transporters thought to be liver-specific, such as OATP1B1 and 1B3, as well as OATP2B1 and 1A2 were expressed in the intestine. However, among OATP transporters, only OATP1A2 was capable of fexofenadine uptake when assessed in vitro. OATP1A2 colocalized with MDR1 to the brush border domain of enterocytes. Consumption of grapefruit juice concomitantly or 2 h before fexofenadine administration was associated with reduced oral fexofenadine plasma exposure, whereas intestinal expression of either OATP1A2 or MDR1 remained unaffected. In conclusion, an array of drug uptake and efflux transporters are expressed in the human intestine. OATP1A2 is likely the key intestinal uptake transporter for fexofenadine absorption whose inhibition results in the grapefruit juice effect. Although short-term grapefruit juice ingestion was associated with reduced fexofenadine availability, OATP1A2 or MDR1 expression was unaffected.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / biosynthesis
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • Adult
  • Aged
  • Aged, 80 and over
  • Beverages / adverse effects*
  • Biological Availability
  • Blotting, Western
  • Carrier Proteins / biosynthesis*
  • Citrus paradisi / adverse effects*
  • Cytochrome P-450 CYP3A / biosynthesis
  • Cytochrome P-450 CYP3A / genetics
  • Cytochrome P-450 Enzyme System / biosynthesis
  • Cytochrome P-450 Enzyme System / genetics
  • Female
  • Fluorescent Antibody Technique
  • Food-Drug Interactions*
  • Histamine H1 Antagonists / blood
  • Humans
  • Immunohistochemistry
  • Intestinal Mucosa / metabolism*
  • Male
  • Middle Aged
  • Organic Anion Transporters / biosynthesis
  • Organic Anion Transporters / genetics
  • Pharmaceutical Preparations / metabolism*
  • RNA / biosynthesis
  • RNA / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Terfenadine / analogs & derivatives
  • Terfenadine / blood


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Carrier Proteins
  • Histamine H1 Antagonists
  • Organic Anion Transporters
  • Pharmaceutical Preparations
  • SLCO1A2 protein, human
  • RNA
  • Terfenadine
  • Cytochrome P-450 Enzyme System
  • fexofenadine
  • Cytochrome P-450 CYP3A