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Intestinal OATP1A2 inhibition as a potential mechanism for the effect of grapefruit juice on aliskiren pharmacokinetics in healthy subjects

Abstract

Purpose

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 AUCinf, AUClast, and Cmax 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.

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Declaration of interests

All authors are employees of Novartis Pharmaceuticals and are eligible for Novartis stock and stock options.

Role of the funding source

This study was supported by Novartis Pharma AG.

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Correspondence to Sam Rebello.

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Rebello, S., Zhao, S., Hariry, S. et al. Intestinal OATP1A2 inhibition as a potential mechanism for the effect of grapefruit juice on aliskiren pharmacokinetics in healthy subjects. Eur J Clin Pharmacol 68, 697–708 (2012). https://doi.org/10.1007/s00228-011-1167-4

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  • DOI: https://doi.org/10.1007/s00228-011-1167-4

Keywords

  • Aliskiren
  • Grapefruit juice
  • Apple juice
  • Orange juice
  • Organic anion transporting polypeptide transporter