approved by the U.S. Food and Drug Administration (FDA) in November 1997 for the treatment of obesity. Sibutramine is reported to be a prodrug to two active metabolites, desmethylsibutramine (M1; BTS-54354) and didesmethylsibutramine (M2; BTS-54505), with much greater potency as monoamine reuptake inhibitors. Further studies have indicated that the (R)-enantiomers of each metabolite exert significantly stronger anorectic effects than the (S)-enantiomers. Unlike other serotonergic appetite suppressants like fenfluramine, sibutramine and its metabolites have only low and likely inconsequential affinity for the 5-HT2B receptor. Pharmacokinetics Sibutramine is well absorbed from the gastrointestinal tract (77%), but undergoes considerable first-pass metabolism, reducing its bioavailability. The drug itself reaches its peak plasma level after 1 hour and has also a half-life of 1 hour. Sibutramine is metabolized by cytochrome P450 isozyme CYP3A4 into two pharmacologically-active primary and secondary amines (called active metabolites 1 and 2) with half-lives of 14 and 16 hours, respectively. Peak plasma concentrations of active metabolites 1 and 2 are reached after three to four hours. The following metabolic pathway mainly results in two inactive conjugated and hydroxylated metabolites (called metabolites 5 and 6). Metabolites 5 and 6 are mainly excreted in the urine. Chemistry Sibutramine has usually been used in the form of the hydrochloride monohydrate salt. Detection in body fluids Sibutramine and its two active N-demethylated metabolites may be measured in biofluids by liquid chromatography-mass spectrometry. Plasma levels of these three species are usually in the 1–10 μg/L range in persons undergoing therapy with the drug. The parent compound and norsibutramine are often not detectable in urine, but dinorsibutramine is generally present at concentrations of >200 μg/L. Society and culture Regulatory approval, 1997-2010 Sibutramine was originally developed in 1988 by Boots in Nottingham, UK,/ and marketed by Knoll Pharmaceuticals after BASF/Knoll AG purchased the Boots Research Division in 1995. It was classified as a Schedule IV controlled substance in the United States. In 1997, the US FDA approved it for weight loss and maintenance of weight loss in people with a BMI greater than or equal to 30 kg/m2 or for people with a BMI ≥27 kg/m2 who have other cardiovascular risk factors. It was manufactured and marketed by Abbott Laboratoriess. It was sold under a variety of brand names including Reductil, Meridia, Siredia, and Sibutrex. In 2002, studies looked into reports of sudden death, heart failure, renal failure and gastrointestinal problems. Despite a 2002 petition by Ralph Nader-founded