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Riboflavin (vitamin B 2 ) has been proposed as a biomarker for breast cancer resistance protein (BCRP) activity. In recent studies in mice, cynomolgus monkeys, and humans, BCRP‐inhibiting drugs increased the plasma concentration of riboflavin. We showed recently that ticagrelor inhibits BCRP and raises the plasma concentrations of the BCRP substrate rosuvastatin in healthy volunteers. In the same drug–drug interaction study, we now investigated whether ticagrelor affects the plasma concentrations of riboflavin. Intake of 90 mg ticagrelor increased the ratio between the peak plasma riboflavin concentration and the fasting riboflavin concentration before ticagrelor administration by 1.20‐fold (90% confidence interval, 1.10–1.32; P = 0.006) compared to placebo. In vitro , riboflavin was transported by BCRP and multidrug‐resistance‐associated protein 4 (MRP4) but no clear transport was observed by MRP2, MRP3, or the P‐glycoprotein. Moreover, ticagrelor inhibited the transport of riboflavin in BCRP‐ and MRP4‐expressing membrane vesicles with unbound 50% inhibitory concentrations of 0.020 and 1.1 μM, respectively. Based on vesicle and tissue protein expression data, the small intestinal MRP4‐mediated efflux clearance of riboflavin (1.2–1.4 nL/min/mg) was estimated to be similar to that mediated by BCRP (0.23–1.3 nL/min/mg). As MRP4 is expressed in the basolateral membrane of enterocytes, it may facilitate the absorption of riboflavin and impair the utility of riboflavin as a biomarker of intestinal BCRP. To conclude, ticagrelor modestly raises the plasma concentration of riboflavin probably by inhibiting intestinal BCRP. Inhibition of intestinal MRP4 may have reduced the absorption of riboflavin and limited the effect of ticagrelor on riboflavin levels.
Deng et al. (Mon,) studied this question.