Submitted to: Journal of Clinical Pharmacology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/18/2013
Publication Date: 9/1/2013
Citation: Won, C.S., Lan, T., Vandermolen, K.M., Dawson, P.A., Oberlies, N.H., Widmer, W.W., Scarlett, Y.V., Paine, M.F. 2013. A modified grapefruit juice eliminates two compound classes as major mediators of the Grapefruit Juice-Fexofenadine Interaction: an In Vitro-In Vivo 'Connect'. Journal of Clinical Pharmacology. 53(9):982-990. Interpretive Summary: Grapefruit juice from concentrate treated to remove furanocoumarins (FC) and methoxylated flavones (MF) but retain flavanone glycosides was tested along with untreated grapefruit juice from the same concentrate in a clinical trial and in-vitro study for effect on inhibition of fexofenadine absorption by intestinal organic anion transporting polypeptides (OATPs). Both juices reduced fexofenadine absorption by approximately 25% compared to water, indicating FCs and MFs are not major mediators in the GFJ-fexofenadine interaction.
Technical Abstract: The grapefruit juice (GFJ)-fexofenadine interaction involves inhibition of intestinal organic anion transporting polypeptide (OATP)-mediated active uptake of fexofenadine by GFJ, manifesting as a decrease in systemic drug exposure. Flavonoids, furanocoumarins, and polymethoxyflavones have been identified as OATP inhibitors in vitro. Only the flavonoid naringin has been shown to contribute to the interaction in vivo. Evaluate furanocoumarins and polymethoxyflavones as enteric OATP inhibitors by comparing effects of a GFJ devoid of furanocoumarins and polymethoxyflavones (mGFJ) to effects of the original GFJ on fexofenadine disposition in healthy volunteers and OATP-transfected cells. Healthy volunteers (n=18) received fexofenadine (120 mg) with water, GFJ, or mGFJ (240 mL) by randomized, three-way crossover design. Plasma was collected from 0-72 h. Each phase was separated by =10 d. Effects of juice extracts on estrone 3-sulfate (E1S) and fexofenadine uptake were compared in OATP1A2- and OATP2B1-transfected cells. Initial in vitro studies with E1S predicted similar OATP1A2/2B1 inhibitory behavior between both juices (~50% inhibition vs. vehicle). Compared to water, both juices decreased fexofenadine geometric mean AUC and Cmax by ~25% (p < 0.01), with no effect on terminal half-life (p > 0.03), in human subjects. Follow-up in vitro experiments with fexofenadine showed similar inhibition of OATP1A2 by both juices (~25% vs. vehicle) but no uptake by OATP2B1. Inhibition of enteric OATP-mediated uptake by GFJ and mGFJ extracts in vitro was consistent with clinical observations. Similar effects by both juices on fexofenadine pharmacokinetics indicate furanocoumarins and polymethoxyflavones are not major mediators of the GFJ-fexofenadine interaction.