Benfluorex metabolism complemented by electrochemistry-mass spectrometry

Stereoselective Analysis of the Antiseizure Activity of Fenfluramine and Norfenfluramine in Mice: Is l-Norfenfluramine a Better Follow-Up Compound to Racemic-Fenfluramine?

“…Abbreviations: N, number of animals protected (seizure activity tests) or number of animals displaying motor impairment; T, number of animals tested. 1 Death following tonic extension in four or 2 in two animals; 3 clonic seizures in four animals, 4 tremors in eight animals; 5 cold tails in six or 6 in five animals; 7 four mice soft to touch; 8 ataxia, 9 unable to grasp rotarod and 10 tremors in three animals; 11 unable to grasp rotarod in eight animals; 12 death following tonic extension in one animal; 13 tremors in nine animals; 14 unable to grasp rotarod in two animals; 15 tremors in four animals; 16 ataxia in eight animals; 17 unable to grasp rotarod in fourteen animals; 18 stretching and rolling in one animal; 19 death without tonic extension in one animal; 20 tremors and 21 severe tremors in two animals; 22 tremors in six animals; 23 loss of righting reflex in one animal; 24 one animal died during test without seizure; 25 tremors in five animals. * Values in brackets are 95% confidence intervals (95%CI) determined using probit analysis.…”

“…In particular, appetite suppression can be ascribed mainly to the d -enantiomers of fenfluramine and norfenfluramine [ 5 , 9 ], whereas cardiovascular toxicity can be ascribed mainly to the activation of 5-HT 2B receptors by d -norfenfluramine [ 5 , 7 , 16 , 17 , 18 , 19 ]. d -Norfenfluramine and l -norfenfluramine are also the major circulating metabolites of the fenfluramine analogue benfluorex ((±)-N-(2-benzoyloxyethy1)-norfenfluramine, Mediator ® ), which was approved in France as an adjuvant antidiabetic and withdrawn in 2009 due to its association with valvular heart disease and pulmonary hypertension [ 3 , 18 , 19 , 20 ].…”

Pharmacokinetics of d‐ and l‐norfenfluramine following their administration as individual enantiomers in rats

“…In addition, d ‐ and l ‐fenfluramine are biotransformed in the body to the corresponding de‐ethylated active metabolites d ‐ and l ‐norfenfluramine, which also differ in their pharmacological profiles 9,10 . Although both fenfluramine and norfenfluramine enantiomers possess anticonvulsant activity in animal models of seizures and epilepsy, 10,11 d ‐fenfluramine and d ‐norfenfluramine are thought to contribute to appetite suppressant activity, whereas d ‐norfenfluramine is considered to be primarily responsible for the cardiovascular toxicity that led to the demise of fenfluramine and d ‐fenfluramine as anorexic agents in 1997, as well as the structurally related benfluorex (a prodrug of d‐ and l‐ norfenfluramine) in 2009 9,12 . Despite these considerations, the vast majority of pharmacokinetic studies conducted with fenfluramine have used non‐enantioselective assays, which fail to differentiate between the four active chemical entities present in the systemic circulation following the administration of fenfluramine 6 …”