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 study was to determine whether ondansetron could serve as a perpetrator drug causing transporter-mediated drug-drug interactions in humans. Twelve unrelated male healthy Chinese volunteers were enrolled into a prospective, randomized, double-blind, 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 C_max of metformin compared with placebo (18.3 ± 5.05 versus 15.2 ± 3.23; P = 0.006) and apparently decreased the renal clearance of metformin by 37% as compared with placebo (P = 0.001). Interestingly, ondansetron treatment also statistically significantly improved glucose tolerance in subjects, as indicated by the smaller glucose area under the curve in the oral glucose tolerance test (10.4 ± 1.43) as compared with placebo (11.5 ± 2.29 mmol∙mg/l) (P = 0.020). It remains possible that ondansetron itself may 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.