title: Intestinal OATP1A2 inhibition as a potential mechanism for the effect of grapefruit juice on aliskiren pharmacokinetics in healthy subjects.
abstract: OBJECTIVE
  To conduct a mechanistic investigation of the interaction between aliskiren and grapefruit juice in healthy subjects.
  
  
  METHODS
  Twenty-eight subjects received an oral dose of aliskiren 300 mg (highest recommended clinical dose) with 300 mL of either water or grapefruit juice in a two-way crossover design. Safety and pharmacokinetic analyses were performed. In vitro studies were performed in HEK293 cells to investigate the role of organic anion transporting polypeptide (OATP) transporter-mediated uptake of aliskiren.
  
  
  RESULTS
  Co-administration of a single dose of aliskiren with grapefruit juice decreased the plasma concentration of aliskiren, with mean decreases in the AUC(inf), AUC(last), and C(max) of 38, 37, and 61%, respectively. The uptake of [¹⁴C]aliskiren into OATP2B1-expressing cells was essentially the same as that into control cells, and the inhibitor combination atorvastatin and rifamycin had no effect on [¹⁴C]aliskiren accumulation in either cell type. The uptake of [¹⁴C]aliskiren and [³H]fexofenadine was linear in OATP1A2-expressing cells and was reduced by naringin, with IC₅₀ values of 75.5 ± 11.6 and 24.2 ± 2.0 μM, respectively.
  
  
  CONCLUSIONS
  Grapefruit juice decreases exposure of aliskiren partially via inhibition of intestinal OATP1A2.
authors: Translational Sciences, Novartis Institute for Biomedical Research, One Health Plaza, Bldg 438-3410, East Hanover, NJ 07936-1080, USA. sam.rebello@novartis.com
authors: Sam
authors: S
authors: Rebello
authors: Sally
authors: S
authors: Zhao
authors: Sam
authors: S
authors: Hariry
authors: Marion
authors: M
authors: Dahlke
authors: Natalya
authors: N
authors: Alexander
authors: Arpine
authors: A
authors: Vapurcuyan
authors: Imad
authors: I
authors: Hanna
authors: Venkateswar
authors: V
authors: Jarugula
mesh_terms: D000328:Adult; D000577:Amides / Q000009:adverse effects / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D000959:Antihypertensive Agents / Q000009:adverse effects / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D001628:Beverages / Q000009:adverse effects* / Q000032:analysis; D001692:Biological Transport / Q000187:drug effects; D032083:Citrus paradisi / Q000737:chemistry*; D018592:Cross-Over Studies; D044950:Flavanones / Q000032:analysis / Q000494:pharmacology; D018565:Food-Drug Interactions; D005638:Fruit / Q000737:chemistry; D005650:Fumarates / Q000009:adverse effects / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D057809:HEK293 Cells; D006207:Half-Life; D006801:Humans; D007413:Intestinal Mucosa / Q000201:enzymology*; D008297:Male; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D016593:Terfenadine / Q000031:analogs & derivatives / Q000378:metabolism; D055815:Young Adult; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D000959:Antihypertensive Agents; D044950:Flavanones; D005650:Fumarates; D027361:Organic Anion Transporters; D011994:Recombinant Proteins; D016593:Terfenadine; D000092502:Renin Inhibitors; C512988:SLCO1A2 protein, human; C446481:aliskiren; C093230:fexofenadine; C005274:naringin