Effect of Ondansetron on Metformin Pharmacokinetics and Response in Healthy Subjects

Abstract

The 5-hydroxytryptamine-3 (5-HT 3 ) 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 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 C max of metformin compared with placebo (18.3 6 5.05 versus 15.2 6 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 6 1.43) as compared with placebo (11.5 6 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.

High‐volume continuous venovenous hemodiafiltration plus resin hemoperfusion improves severe metformin‐associated toxicity

“…However, there is large variability in the hypoglycemic response to metformin. The most frequent side‐effect of metformin is gastrointestinal irritation, including nausea, vomiting, diarrhea and cramps. Metformin taken alone is unlikely to cause glycopenia in general patients; however, metformin overdose induces hypoglycemia and lactic acidosis.…”

A Whole-Body Physiologically Based Pharmacokinetic Model Characterizing Interplay of OCTs and MATEs in Intestine, Liver and Kidney to Predict Drug-Drug Interactions of Metformin with Perpetrators

“…The parameter estimation method was the first order conditional estimation of Lindstrom-Bates (FOCE L-B) [115]. Together with standard deviation of intra-individual error, Vmax,OCT3, CLint,up,OCT1, CLint,up,OCT2, CLint,efflux,MATEs, and Kti, which were regarded as random effect pa- [13,15,16,19,20,27,68,69,84,. (c) Visual predictive checks (VPCs) of metformin plasma concentrations to time in 500 mg oral administration for human; solid line, the 50th percentiles; dashed lines, the 5 and 95th percentiles of the simulated populations; the shaded area, 90% confidence intervals of the simulated concentrations of the 5, 50 and 95th percentiles; and the point, observations, which were cited from [27,69,91,93,97,114].…”

Pharmacokinetics of R‐(−)ondansetron compared with that of S‐(−)ondansetron in rats using an LC–MS/MS method

“…The pharmacokinetics of racemic ondansetron and R‐ ond and S‐ ond by chiral separation has been reported (Christofaki & Papaioannou, , Lemon et al, , Li et al, , Liu, Dai, Zhong, & Chen, , Musshoff, Madea, Stüber, & Stamer, , Pang et al, , Stamer et al, , Vandenberg et al, , Yan et al, , Yang & Lee, ). However, no R‐ ond pharmacokinetics following administration of a single ondansetron enantiomer has been reported.…”