Induction of Glucose Intolerance by Acute Administration of Rimonabant

Mandhane, Sanjay N.; Nayak, Prasant; Soni, Durgesh; Jain, Shakti; Ashton, John C.; Thennati, Rajamannar

doi:10.1159/000337731

Cited by 3 publications

(2 citation statements)

References 61 publications

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“…However, it is not clear whether ondansetron alone can affect the plasma glucose levels in Mandhane et al's (2012) study. Another study showed that pretreatment with ondansetron was able to reduce the hyperglycemic response induced by central administration of quipazine; however, ondansetron injection alone into the third ventricle had no effect on plasma glucose concentrations in rodents (Carvalho et al, 2005).…”

Section: Discussionmentioning

confidence: 78%

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Effect of Ondansetron on Metformin Pharmacokinetics and Response in Healthy Subjects

Yang

Guo

et al. 2016

Drug Metabolism and Disposition

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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.

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Section: Discussionmentioning

confidence: 78%

“…One previous study showed that ondansetron could significantly suppress rimonabant-induced increases in blood glucose, particularly at 40 minutes and 120 minutes in OGTT in mice (Mandhane et al, 2012). However, it is not clear whether ondansetron alone can affect the plasma glucose levels in Mandhane et al's (2012) study.…”

Section: Discussionmentioning

confidence: 90%

Effect of Ondansetron on Metformin Pharmacokinetics and Response in Healthy Subjects

Yang

Guo

et al. 2016

Drug Metabolism and Disposition

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Cannabinoid receptor 1 antagonist treatment induces glucagon release and shows an additive therapeutic effect with GLP-1 agonist in diet-induced obese mice

Patel

Joharapurkar

Patel

et al. 2014

Can. J. Physiol. Pharmacol.

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Cannabinoid 1 (CB1) receptor antagonists reduce body weight and improve insulin sensitivity. Preclinical data indicates that an acute dose of CB1 antagonist rimonabant causes an increase in blood glucose. A stable analog of glucagon-like peptide 1 (GLP-1), exendin-4 improves glucose-stimulated insulin secretion in pancreas, and reduces appetite through activation of GLP-1 receptors in the central nervous system and liver. We hypothesized that the insulin secretagogue effect of GLP-1 agonist exendin-4 may synergize with the insulin-sensitizing action of rimonabant. Intraperitoneal as well as intracerebroventricular administration of rimonabant increased serum glucose upon glucose challenge in overnight fasted, diet-induced obese C57 mice, with concomitant rise in serum glucagon levels. Exendin-4 reversed the acute hyperglycemia induced by rimonabant. The combination of exendin-4 and rimonabant showed an additive effect in the food intake, and sustained body weight reduction upon repeated dosing. The acute efficacy of both the compounds was additive for inducing nausea-like symptoms in conditioned aversion test in mice, whereas exendin-4 treatment antagonized the effect of rimonabant on forced swim test upon chronic dosing. Thus, the addition of exendin-4 to rimonabant produces greater reduction in food intake owing to increased aversion, but reduces the other central nervous system side effects of rimonabant. The hyperglucagonemia induced by rimonabant is partially responsible for enhancing the antiobesity effect of exendin-4.

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Interactions with Drugs and Dietary Supplements Used For Weight Loss

Jordan¹

2013

Drug Discovery

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Induction of Glucose Intolerance by Acute Administration of Rimonabant

Cited by 3 publications

References 61 publications

Effect of Ondansetron on Metformin Pharmacokinetics and Response in Healthy Subjects

Effect of Ondansetron on Metformin Pharmacokinetics and Response in Healthy Subjects

Cannabinoid receptor 1 antagonist treatment induces glucagon release and shows an additive therapeutic effect with GLP-1 agonist in diet-induced obese mice

Interactions with Drugs and Dietary Supplements Used For Weight Loss

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