Intestinal Drug Transporter Expression and the Impact of Grapefruit Juice in Humans
2007/01/10 by Hartmut Glaeser, H Glaeser, David G. Bailey +17 · 35 citations
Medicine · Pharmacology, Toxicology and Pharmaceutics · #Drug Transport and Resistance Mechanisms #Pharmacological Effects and Toxicity Studies #Pharmacogenetics and Drug Metabolism
paper · doi:10.1038/sj.clpt.6100056
Abstract
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.
Citations
Cited by
- Naringin is a Major and Selective Clinical Inhibitor of Organic Anion-Transporting Polypeptide 1A2 (OATP1A2) in Grapefruit Juice
- Fruit Juices as Perpetrators of Drug Interactions: The Role of Organic Anion–Transporting Polypeptides
- Exposure of Fexofenadine, but Not Pseudoephedrine, Is Markedly Decreased by Green Tea Extract in Healthy Volunteers
- Influence of the flavonoids apigenin, kaempferol, and quercetin on the function of organic anion transporting polypeptides 1A2 and 2B1
- Protein kinase C regulates the internalization and function of the human organic anion transporting polypeptide 1A2
- Interplay between the Nuclear Receptor Pregnane X Receptor and the Uptake Transporter Organic Anion Transporter Polypeptide 1A2 Selectively Enhances Estrogen Effects in Breast Cancer
- Organic anion transporting polypeptides: Pharmacology, toxicology, structure, and transport mechanisms
- Stable and functional human intestinal epithelium derived from induced pluripotent stem cells
- The Expression and Function of Organic Anion Transporting Polypeptides in Normal Tissues and in Cancer
- Role of Drug Efflux and Uptake Transporters in Atazanavir Intestinal Permeability and Drug-Drug Interactions
- Interplay between the nuclear receptor pregnane X receptor and the uptake transporter organic anion transporter polypeptide 1A2 selectively enhances estrogen effects in breast cancer. [europepmc]
- Overexpression of OATP1B3 confers apoptotic resistance in colon cancer. [europepmc]
- Pharmacogenetics of the organic anion transporting polypeptide 1A2. [europepmc]
- ESRD impairs nonrenal clearance of fexofenadine but not midazolam. [europepmc]
- Xenobiotic, bile acid, and cholesterol transporters: function and regulation. [europepmc]
- Organic anion transporting polypeptide 1a/1b-knockout mice provide insights into hepatic handling of bilirubin, bile acids, and drugs. [europepmc]
- The effect of grapefruit juice on drug disposition. [europepmc]
- Environmental and genetic factors affecting transport of imatinib by OATP1A2. [europepmc]
- Gut bitter taste receptor signalling induces ABCB1 through a mechanism involving CCK. [europepmc]
- Primary and secondary thyroid hormone transporters. [europepmc]
- The expression and function of organic anion transporting polypeptides in normal tissues and in cancer. [europepmc]
- Mechanisms underlying food-drug interactions: inhibition of intestinal metabolism and transport. [europepmc]
- Insights into dietary flavonoids as molecular templates for the design of anti-platelet drugs. [europepmc]
- Nuclear-receptor-mediated regulation of drug- and bile-acid-transporter proteins in gut and liver. [europepmc]
- Mass spectrometry-based targeted proteomics as a tool to elucidate the expression and function of intestinal drug transporters. [europepmc]
- Organic anion-transporting polypeptides. [europepmc]
- Mutual interactions between flavonoids and enzymatic and transporter elements responsible for flavonoid disposition via phase II metabolic pathways. [europepmc]
- Role of Organic Anion-Transporting Polypeptides (OATPs) in Cancer Therapy. [europepmc]
- Inhibitory Effects of Green Tea and (-)-Epigallocatechin Gallate on Transport by OATP1B1, OATP1B3, OCT1, OCT2, MATE1, MATE2-K and P-Glycoprotein. [europepmc]
- Cyanobacterial Toxins of the Laurentian Great Lakes, Their Toxicological Effects, and Numerical Limits in Drinking Water. [europepmc]
- Food-drug interactions precipitated by fruit juices other than grapefruit juice: An update review. [europepmc]
- Organic Anion Transporting Polypeptides: Emerging Roles in Cancer Pharmacology. [europepmc]
- Dietary Flavonoids for Immunoregulation and Cancer: Food Design for Targeting Disease. [europepmc]
- Quantitative Proteomics of Clinically Relevant Drug-Metabolizing Enzymes and Drug Transporters and Their Intercorrelations in the Human Small Intestine. [europepmc]
- A guide to plasma membrane solute carrier proteins. [europepmc]
Related