Effect of Ondansetron on Metformin Pharmacokinetics and Response in Healthy Subjects

Abstract

The 5-hydroxytryptamine-3 (5-HT3) receptor antagonists such as ondansetron have been used to prevent and treat nausea and vomiting for over 2 decades. This studywas to determinewhether ondansetron could serve as a perpetrator drug causing transporter-mediated drugdrug interactions in humans. Twelve unrelated male healthy Chinese volunteers were enrolled into a prospective, randomized, doubleblind, crossover study to investigate the effects of ondansetron or placebo on the pharmacokinetics of and the response to metformin, a well-characterized substrate of organic cation transporters and multidrug and toxin extrusions (MATEs). Ondansetron treatment caused a statistically significantly higher Cmax of metformin compared with placebo (18.365.05 versus 15.263.23; P = 0.006) and apparently decreased the renal clearance ofmetformin by 37% as compared with placebo (P = 0.001). Interestingly, ondansetron treatment also statistically significantly improved glucose tolerance in subjects, as indicated by thesmaller glucose area under the curve in the oral glucose tolerance test (10.4 6 1.43) as compared with placebo (11.5 6 2.29 mmolmg/l) (P = 0.020). It remains possible that ondansetron itselfmay affect glucose homeostasis in human subjects, but our clinical study, coupled with our previous findings in cells and in animal models, indicates that ondansetron can cause a drug-drug interaction via its potent inhibition of MATE transporters in humans.