6 ,7 -dihydroxybergamottin (DHB) is one of the components of grapefruit juice and is a known irreversible inhibitor of intestinal cytochrome P450 3A (CYP3A). A single serving (240 mL) of grapefruit juice (GFJ) contains less than or equal to 5 mg of DHB. The pharmacokinetic boosting effect of GFJ has fueled the marketing of dietary supplements labeled to contain DHB e.g. DHB 300 (TM) and Trisorbagen that enhance absorption naturally, While these supplements have been found to inhibit CYP3A activity, the DHB content in these supplements is much lower than that, of GFJ. Moreover, the effects of such supplements on the pharmacokinetics of CYP3A-metabolized drugs are largely unknown. This single-center, open-label, randomized, 3-period, single-dose, crossover study in healthy volunteers will compare the drug interaction risk of a dietary supplement known to affect CYP3A with GFJ. The primary objective of this study is to compare the effects of a supplement known to affect CYP3A (e.g.Trisorbagen) with those of GFJ and water on the pharmacokinetics of two model substrates, the FDA-recommended CYP3A probe substrate midazolam, and the dual CYP3A/P-glycoprotein (P-gp) substrate loperamide. This dual-probe substrate approach to assess drug interaction risk will provide mechanistic insight into any interaction observed. Eligible volunteers (n=12) will undergo 3 phases, each comprising an exposure visit and 4 subsequent post-exposure visits to collect blood and urine over 72 or 12 hours, respectively. Exposure visits will be scheduled at least 2 weeks apart to allow washout between the phases. At each exposure visit, participants will be administered oral doses of midazolam hydrochloride (2.5 mg) and loperamide (16 mg) concomitantly with water (240 mL), GFJ (240 mL), or Trisorbagen (with 240 mL water) according to a randomized treatment sequence. Blood and urine will be collected pre-dose and post-dose over 72 (blood) or 12 (urine) hours for subsequent analyses of relevant pharmacokinetic outcomes of each probe substrate, including the primary endpoints area under the concentration-time curve from time zero (pre-dose) to infinity (AUC0-inf) and maximum observed concentration (Cmax). Secondary endpoints include geometric means, estimates of treatment differences, within-subject and between-subject treatment variance, as well as the 95% confidence intervals around those estimates.