The contribution of metabolites to the rapid and potent down-regulation of rat cortical β-adrenoceptors by the putative antidepressant sibutramine hydrochloride

Luscombe, Graham; Hopcroft, R H; Thomas, P C; Buckett, W. R.

doi:10.1016/0028-3908(89)90048-8

Cited by 91 publications

(81 citation statements)

References 10 publications

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“…It has been reported that sibutramine and sibutramine analog have similar pharmacokinetics and pharmacological profiles (Hind et al, 1999). In particular, the secondary amine (N-desmethylsibutramine) is more active than the tertiary amine (sibutramine) regarding the inhibition of uptaking of monoamines in vitro (Luscombe et al, 1989). Therefore, it is more important to monitor dietary supplements adulterated with N-desmethylsibutramine.…”

Section: Lc/ms/msmentioning

confidence: 99%

Simultaneous determination of anti‐diabetes/anti‐obesity drugs by LC/PDA, and targeted analysis of sibutramine analog in dietary supplements by LC/MS/MS

Kim

Lee

Yoon

et al. 2009

Biomedical Chromatography

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The safety of dietary supplements is questionable as there have been occasional reports of products contaminated with illegal adulterants. The present study was carried out to develop trustworthy methodologies to screen for six antidiabetic drugs (phenformin, rosiglitazone, glipizide, glimepiride, glybenclamide and gliclazide) and six anti-obesity drugs (ephedrine, fenfluramine, T3, T4, fluoxetine and sibutramine) in dietary supplements. A simultaneous determination method of the 12 drugs by liquid chromatography coupled with a photodiode array (LC/PDA) was established and was validated for linearity (r 2 > 0.99), precision (RSD < < < <13.3%), recoveries (88.8-115.9%) and reproducibility. Sibutramine and its analogs, N-desmethylsibutramine, were subject to further investigation by LC/MS/MS because they were one of the major illegal adulterants. Our proposed method to monitor illegal drug adulterations in dietary supplements using LC/PDA is a simple and reliable, and therefore applicable to routine drug-adulteration screening.

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Section: Lc/ms/msmentioning

confidence: 99%

Simultaneous determination of anti‐diabetes/anti‐obesity drugs by LC/PDA, and targeted analysis of sibutramine analog in dietary supplements by LC/MS/MS

Kim

Lee

Yoon

et al. 2009

Biomedical Chromatography

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“…4,5 It has been further demonstrated that the monoamine uptake inhibition properties of sibutramine in vivo are predominantly mediated by its primary and secondary metabolites. 6 Animal studies have shown that sibutramine reduces food intake in rats when given acutely 7 -9 by enhancing the natural process of satiety. 10,11 Evidence from various studies with selective monoamine reuptake inhibitors and receptor antagonists indicates that hypophagia probably results from 5-HT and NA reuptake inhibition in the CNS.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of the thermogenic effect of Metabolite 2 (BTS 54 505), a major pharmacologically active metabolite of the novel anti-obesity drug, sibutramine

Heal

2002

Int J Obes

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OBJECTIVE:To investigate the pharmacological mechanisms underlying the induction of thermogenesis by Metabolite 2 (M2; BTS 54 505), a major pharmacologically active metabolite of the anti-obesity drug, sibutramine. DESIGN: Adult female Wistar rats were treated with M2 or vehicle, with or without various monoamine receptor antagonists, prazosin, RS79948, metergoline, propranolol and ( þ )butaclamol. MEASUREMENTS: Colonic temperature and food intake at room temperature (21 AE 1 C), thermoregulatory behavioural response, operant responding for exogenous heat at 7 8 C and oxygen consumption at thermoneutrality (29 C). RESULTS: M2 (10 mg=kg, p.o.) significantly increased colonic temperature during the 4.5 h period following drug administration. This effect was abolished by the non-selective 5-HT receptor antagonist, metergoline (1 mg=kg, p.o.), and a 1 -adrenoceptor antagonist, prazosin (1 mg=kg, p.o.), measured at 1.5 -2.5 h post-M2 administration, and was partially antagonized by each antagonist at 3.5 -4.5 h. The non-selective b-adrenoceptor antagonist, propranolol (1 mg=kg, p.o.), had no effect on the M2-induced increase in colonic temperature, whereas at 20 mg=kg (p.o.), propranolol partially inhibited the effect of M2 on colonic temperature. By contrast, the selective a 2 -adrenoceptor antagonist, RS79948 (1 mg=kg, p.o.), and the D2=D1 receptor antagonist, ( þ )butaclamol (200 mg=kg, p.o.), did not alter the effect of M2 on colonic temperature. In the thermoregulatory study, M2 (10 mg=kg, i.p.)-treated rats required significantly less radiant heat at 7 8 C to maintain body temperature, and this effect was not affected by the D2=D1 receptor antagonist ( þ )butaclamol (100 mg=kg 71 , i.p.). The hypophagia induced by M2 (10 mg=kg) measured up to 24 h was partially antagonized by the a 1 -adrenoceptor antagonist, prazosin, whereas metergoline, RS79948, propranolol and ( þ )butaclamol had no effect on M2-induced hypophagia. CONCLUSION: It is concluded that 5-HT, a 1 -and b 3 -adrenoceptors are involved in the induction of thermogenesis by M2, whereas the hypophagic effect is mainly mediated via a 1 -adrenoceptors. These findings are consistent with M2 increasing 5-HT and noradrenaline tone via potent reuptake inhibition which subsequently results in increased efferent sympathetic activity to brown adipose tissue (BAT).

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“…1,2 It is a tertiary amine and when administered to animals and humans, it is rapidly deaminated to form the secondary amine, metabolite 1 and the primary amine, metabolite 2, which are believed to exert the major pharmacological action of the drug. 2,3 Sibutramine has been shown to cause weight loss in humans 4 and rats 5,6 by increasing satiety, thus reducing food intake, 7 but its ability to induce a reduction in body weight is also linked to an increase in mammalian energy expenditure processes. Indeed, acute sibutramine treatment produced an increase in oxygen consumption, basal metabolic rate, and body temperature in rats.…”

Section: Introductionmentioning

confidence: 99%

Sibutramine-dependent brown fat activation in rats: an immunohistochemical study

Giordano

Centemeri²,

Zingaretti

et al. 2002

Int J Obes

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OBJECTIVES:To evaluate morphological aspects and immunohistochemical markers of brown adipose tissue (BAT) activation following chronic treatment with sibutramine, a novel anti-obesity drug which increases thermogenesis and energy expenditure in mammals, and to establish whether chronic sibutramine treatment induces recruitment of BAT in white adipose tissue (WAT) depots. DESIGN: Adult rats were administered 7 mg=kg=day oral sibutramine for 4 weeks. Body weight was monitored daily. At the end of the 4 weeks rats were perfused with buffered paraformaldehyde solution; interscapular BAT and retroperitoneal and epididymal WAT were carefully dissected for weight and volume measurements and processed for light microscopic studies and immunohistochemistry on paraffin-embedded sections. Where possible, semiquantitative morphometric analyses were performed. RESULTS: Chronic sibutramine treatment determined a significant (about 8%) reduction in body weight. Compared with controls, sibutramine-treated rats showed: (1) interscapular brown adipocytes staining more intensely for uncoupling protein 1 (UCP1), the thermogenic mitochondrial protein; (2) a significantly larger number (about 45%) of brown adipocyte nuclei positive for peroxisome proliferator-activated receptor g, the transcription factor driving UCP1 expression; (3) surprisingly, a significant reduction (about 30%) in BAT parenchymal noradrenergic nerve staining; and (4) a significant weight and volume reduction of WAT depots, but no significant signs of transdifferentiation of white into brown adipocytes. CONCLUSION: This study confirms the ability of sibutramine to induce weight loss by selective and sustained activation of BAT in rodents without recruitment of brown fat in WAT depots. The parallel findings of a high level of brown adipocyte activation and low parenchymal noradrenergic innervation are discussed and a possible direct effect of sibutramine and=or its active metabolites on peripheral BAT sympathetic nerve terminals is hypothesized.

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The contribution of metabolites to the rapid and potent down-regulation of rat cortical β-adrenoceptors by the putative antidepressant sibutramine hydrochloride

Cited by 91 publications

References 10 publications

Simultaneous determination of anti‐diabetes/anti‐obesity drugs by LC/PDA, and targeted analysis of sibutramine analog in dietary supplements by LC/MS/MS

Simultaneous determination of anti‐diabetes/anti‐obesity drugs by LC/PDA, and targeted analysis of sibutramine analog in dietary supplements by LC/MS/MS

Mechanism of the thermogenic effect of Metabolite 2 (BTS 54 505), a major pharmacologically active metabolite of the novel anti-obesity drug, sibutramine

Sibutramine-dependent brown fat activation in rats: an immunohistochemical study

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