title: 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 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 Cmax 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.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland (Q.L., H.Y., D.G., J.E.P., Y.S.); Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Hunan, People's Republic of China (Q.L., T.Z., H.Z.) yshu@rx.umaryland.edu qli1026@163.com.
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland (Q.L., H.Y., D.G., J.E.P., Y.S.); Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Hunan, People's Republic of China (Q.L., T.Z., H.Z.).
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland (Q.L., H.Y., D.G., J.E.P., Y.S.); Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Hunan, People's Republic of China (Q.L., T.Z., H.Z.).
authors.forename: Dong
authors.initials: D
authors.lastname: Guo
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland (Q.L., H.Y., D.G., J.E.P., Y.S.); Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Hunan, People's Republic of China (Q.L., T.Z., H.Z.).
authors.forename: Taolan
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland (Q.L., H.Y., D.G., J.E.P., Y.S.); Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Hunan, People's Republic of China (Q.L., T.Z., H.Z.).
authors.forename: James E
authors.initials: JE
authors.lastname: Polli
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland (Q.L., H.Y., D.G., J.E.P., Y.S.); Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Hunan, People's Republic of China (Q.L., T.Z., H.Z.).
authors.forename: Honghao
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland (Q.L., H.Y., D.G., J.E.P., Y.S.); Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Hunan, People's Republic of China (Q.L., T.Z., H.Z.) yshu@rx.umaryland.edu qli1026@163.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Shu
mesh_terms: D000284:Administration, Oral; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004347:Drug Interactions / Q000502:physiology; D064368:Healthy Volunteers; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000097:blood*; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000097:blood*; D017294:Ondansetron / Q000008:administration & dosage / Q000097:blood*; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011446:Prospective Studies; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000008:administration & dosage / Q000097:blood*; D055815:Young Adult
chemical_list: D007004:Hypoglycemic Agents; D027701:Organic Cation Transport Proteins; D058831:Serotonin 5-HT3 Receptor Antagonists; D017294:Ondansetron; D008687:Metformin
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