Monoamine oxidase inhibition is unlikely to be relevant to the risks associated with phentermine and fenfluramine: a comparison with their abilities to evoke monoamine release

Kilpatrick, I.C.; Traut, M; Heal, David J.

doi:10.1038/sj.ijo.0801732

Cited by 21 publications

(17 citation statements)

References 28 publications

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“…Inhibition of MAO produces measurable decreases in plasma 5-HIAA. Several types of evidence obtained in rat nervous tissue suggest that phentermine and fenfluramine do not affect MAO (Baumann et al, 2000;Kilpatrick et al, 2001), and the present data confirm that high i.v. doses of these drugs do not affect plasma 5-HIAA (see Fig.…”

Section: Discussionsupporting

confidence: 80%

Amphetamine Analogs Increase Plasma Serotonin: Implications for Cardiac and Pulmonary Disease

Żółkowska¹,

Rothman²,

Baumann³

2006

J Pharmacol Exp Ther

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Elevations in plasma serotonin (5-HT) have been implicated in the pathogenesis of cardiac and pulmonary disease. Normally, plasma 5-HT concentrations are kept low by transporter-mediated uptake of 5-HT into platelets and by metabolism to 5-hydroxyindoleacetic acid (5-HIAA). Many abused drugs (e.g., substituted amphetamines) and prescribed medications (e.g., fluoxetine) target 5-HT transporters and could thereby influence circulating 5-HT. We evaluated the effects of amphetamines analogs [(Ϯ)-fenfluramine, (Ϯ)-3,4-methylenedioxymethamphetamine, (ϩ)-methamphetamine, (ϩ)-amphetamine, phentermine] on extracellular levels (i.e., plasma levels) of 5-HT and 5-HIAA in blood from catheterized rats. Effects of the 5-HT uptake blocker fluoxetine were examined for comparison. Drugs were tested in vivo and in vitro; plasma indoles were measured using a novel microdialysis method in whole blood. We found that baseline dialysate levels of 5-HT are ϳ0.22 nM, and amphetamine analogs evoke large dose-dependent increases in plasma 5-HT ranging from 4 to 20 nM. The ability of drugs to elevate plasma 5-HT is positively correlated with their potency as 5-HT transporter substrates. Fluoxetine produced small, but significant, increases in plasma 5-HT. Although the drug-evoked 5-HT concentrations are below the micromolar levels required for contraction of pulmonary arteries, they approach concentrations reported to stimulate mitogenesis in pulmonary artery smooth muscle cells. Additional studies are needed to determine the effects of chronic administration of amphetamines on circulating 5-HT.Serotonin (5-hydroxytryptamine, 5-HT) is an endogenous bioactive compound that is widely distributed in neurons, mast cells, enterochromaffin cells, and blood platelets (Cooper et al., 2003;Gershon, 2004). Under normal physiological conditions, plasma 5-HT levels are kept exquisitely low (i.e., Ͻ1 nM) due to transporter-mediated uptake of 5-HT into blood platelets and via metabolism of 5-HT to 5-hydroxyindoleacetic acid (5-HIAA) by monoamine oxidase (MAO). Included among the many physiological effects of 5-HT are mitogenesis and vasoconstriction. Accordingly, altered regulation of 5-HT levels in blood has been implicated in the pathogenesis of cardiac valvular heart disease (VHD) (Robiolio et al., 1995) and primary pulmonary hypertension (PPH) (MacLean et al., 2000). Many substituted amphetamine analogs (e.g., fenfluramine and aminorex) are substrates for 5-HT transporters (SERTs) and release 5-HT from neurons via reversal of SERT (Rothman et al., 1999). One hypothesis to explain the ability of these agents to increase the risk of developing PPH is that they increase plasma 5-HT by stimulating 5-HT release from platelets (i.e., "the 5-HT hypothesis" of PPH) (MacLean et al., 2000). Others have invoked the same mechanism to explain fenfluramine-induced VHD (Fishman, 1999), although a more likely mechanism in this case involves activation of 5-HT 2B receptors by the N-deethylated metabolite of fenfluramine, norfenfluramine (Rothman et al., 2000...

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Section: Discussionsupporting

confidence: 80%

Amphetamine Analogs Increase Plasma Serotonin: Implications for Cardiac and Pulmonary Disease

Żółkowska¹,

Rothman²,

Baumann³

2006

J Pharmacol Exp Ther

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“…Ulus et al (2000) suggested that phentermine and other amphetamine-type stimulants might block MAO activity in vivo. While several lines of evidence obtained in rats suggest that this is not the case (Baumann et al, 2000;Kilpatrick et al, 2001), the present study afforded a valuable opportunity to test the hypothesis that pharmacological doses of phentermine and related stimulants block MAO in nonhuman primates. As reported in Figure 5, (þ)-amphetamine, phentermine, and (6)-ephedrine failed to reduce the levels of acid metabolites of DA and 5-HT, namely, DOPAC and 5-HIAA, respectively.…”

Section: Discussionmentioning

confidence: 88%

Noradrenergic and dopaminergic effects of (+)‐amphetamine‐like stimulants in the baboon Papio anubis

Alexander

Rothman

Baumann

et al. 2005

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(+)-Amphetamine, (+/-)-ephedrine, and phentermine are commonly used appetite suppressants that release monoamines from nerve cells by acting as substrates for biogenic amine transporters. One key difference among the three drugs is their selectivity for norepinephrine (NE) release vs. dopamine (DA) release. The NE/DA selectivity ratios for these drugs as determined in vitro [(EC50 NE(-1))/(EC50 DA(-1))] are (+/-)-ephedrine (18.6) > phentermine (6.7) > (+)-amphetamine (3.5). The in vitro data suggest that when administered in vivo, these stimulants might differ in their ability to release DA from nerve terminals in the brain. To test this hypothesis, noradrenergic effects (i.e., plasma NE) and dopaminergic effects (i.e., central DA release) were assessed when each drug was administered intravenously (1.5 mg/kg) to anesthetized baboons. Central DA release was determined via positron emission tomography using the method of [11C]raclopride displacement. In the present investigation, high doses of these stimulants increased plasma NE and DA in parallel, but only (+)-amphetamine released central DA from neurons and decreased plasma prolactin. None of the drugs altered plasma amine metabolite levels, indicating no inhibition of monoamine oxidase activity at the administered doses. Plasma drug levels measured in baboons were higher than those measured in human patients taking prescribed doses of the drugs. Viewed collectively, the present data indicate that typical clinical doses of phentermine and (+/-)-ephedrine may not release central DA in humans, a hypothesis that should ultimately be tested in controlled clinical studies.

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“…In any event, phentermine has already been shown to be essentially inactive as a 5HT uptake inhibitor in vitro 14,17 (IC 50 ¼ 11 -14 mM). As for alternative mechanisms, although inhibition of monoamine oxidase (MAO) can yield relatively rapid elevations of extracellular 5HT, 18 these are usually persistent and can continue to rise for up to 5 h. 18,19 Again, however, phentermine has been shown to be extremely weak as an inhibitor of MAO A (IC 50 ¼ 100 -200 mM) 20,21 or MAO B (IC 50 ¼ 300 -900 mM). 20,21 Thus, the route by which phentermine evokes increases in extracellular 5HT in vivo is unclear.…”

Section: Discussionmentioning

confidence: 99%

Additive effects on rat brain 5HT release of combining phentermine with dexfenfluramine

et al. 2001

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OBJECTIVE AND DESIGN:This study examined the effects of the anti-obesity agents, phentermine and dexfenfluramine given alone or in combination, on in vitro and in vivo 5HT release from rat brain tissue. RESULTS: In vitro, phentermine was without effect on basal [ 3 H]5HT efflux from hypothalamic slices whereas dexfenfluramine (10 mM) evoked a 131% increase in [ 3 H]5HT release. In combination, the two drugs did not alter [ 3 H]5HT release beyond that caused by dexfenfluramine alone. At pharmacologically equivalent doses, phentermine (5.7 mg=kg, i.p.) caused a rapid, modest elevation, and dexfenfluramine (3 mg=kg, i.p.) a larger but equally rapid elevation of extracellular 5HT in the microdialysates from the rat anterior hypothalamus. In combination, the increase in extracellular 5HT evoked by these drugs was not significantly greater than the sum of their individual effects. CONCLUSIONS: This study provides evidence that phentermine's actions are not restricted to catecholamine systems and indicates that combining phentermine with dexfenfluramine results in an additive increase in neuronal 5HT release.

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Monoamine oxidase inhibition is unlikely to be relevant to the risks associated with phentermine and fenfluramine: a comparison with their abilities to evoke monoamine release

Cited by 21 publications

References 28 publications

Amphetamine Analogs Increase Plasma Serotonin: Implications for Cardiac and Pulmonary Disease

Amphetamine Analogs Increase Plasma Serotonin: Implications for Cardiac and Pulmonary Disease

Noradrenergic and dopaminergic effects of (+)‐amphetamine‐like stimulants in the baboon Papio anubis

Additive effects on rat brain 5HT release of combining phentermine with dexfenfluramine

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