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

Rebello, Sam and Zhao, Sally and Hariry, Sam and Dahlke, Marion and Alexander, Natalya and Vapurcuyan, Arpine and Hanna, Imad and Jarugula, Venkateswar (2011) Intestinal OATP1A2 inhibition as a potential mechanism for the effect of grapefruit juice on aliskiren pharmacokinetics in healthy subjects. European journal of clinical pharmacology. ISSN 0031-6970

Abstract

We describe a mechanistic investigation of drug–drug interaction between aliskiren and grapefruit juice in healthy subjects. Twenty-eight subjects received an oral dose of aliskiren 300 mg (highest recommended clinical dose) with 300 mL water or grapefruit juice concentrate in a two-way crossover design. Safety and pharmacokinetic analyses were performed during each treatment period. Concomitant administration of a single dose of aliskiren with grapefruit juice decreased plasma concentration of aliskiren. The mean decrease in AUCinf, AUClast and Cmax was 38%, 37% and 61%, respectively. Aliskiren administered alone or in combination with grapefruit juice was well tolerated in healthy subjects. To provide mechanistic evidence for the grapefruit juice effect, in vitro transport studies were performed using OATP-subtype transfected HEK293 cells. The uptake of [14C]aliskiren into OATP2B1-expressing cells was essentially the same as that into control cells, and the inhibitor combination, atorvastatin (10 µM) and rifamycin SV (20 µM), had no effect of [14C]aliskiren accumulation in either cell line. The uptake of [14C]aliskiren and [3H]fexofenadine was linear in OATP1A2-expressing cells, and was reduced by naringin (a component of grapefruit juice) with an IC50 of 75.5 ± 11.6 μM and 24.2 ± 2.0 μM, respectively. In conclusion, grapefruit juice decreases exposure of aliskiren via inhibition of intestinal OATP1A2 and it is likely that this effect is not clinically relevant.

Item Type: Article
Additional Information: Comments from Dan Howard addressed by changing the title.
Keywords: aliskiren, grapefruit juice, apple juice, orange juice, organic anion transporting polypeptide transporter
Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15
URI: https://oak.novartis.com/id/eprint/5364

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