Metabolism and excretion of diethylpropion in man under acidic urine conditions

Abstract

After oral administration, diethylpropion is rapidly and extensively metabolized in man by N-de-ethylation and stereoselective carbonyl reduction. The unchanged drug excreted in acidic urine represents about 2% of the dose, while the total metabolites determined account for some 85%. The excretion curves indicate that the probable contribution of the parent compound to the observed activity is small. The major metabolites, together representing about 70% of the dose, are N-ethylaminopropiophenone, (+)-N-diethylnorpseudoephedrine, (+)-N-ethylnorpseudoephedrine, (-)-norephedrine and (-)-norpseudoephedrine. The other stereoisomers of the three amino-alcohols, and aminopropiophenone, are present in minor amounts.Diethylpropion (Amfepramone D.C.I.) (I, Fig. l), an anorectic agent (e.g. Boissier, 1962;Eiden, 1970) is completely absorbed from the human gastrointestinal tract and excreted exclusively via the renal pathway (Schreiber, Bozian & others, 1965). It undergoes extensive metabolism, the main metabolic routes being N-dealkylation, keto reduction and deamination, with para-hydroxylation occurring only to a small extent (Schreiber, Min & others, 1968). However, because the pooled urine samples were made alkaline (pH 12) and extracted over 24 h, some qualitative and quantitative aspects of these studies are questionable, since diethylpropion (I) and its aminoketone metabolites (11 and EI) are unstable under alkaline conditions (Hossie, 1970). Consequently, some of the "metabolites" detected by Schreiber & others (1968) are probably artifacts.Hossie (1970) showed that the two major metabolic pathways are N-dealkylation (compounds II, 111, V and VI account for some 60% of the dose) and reduction (compounds IVY V and VI account for about 40% of the dose). No N-oxides or glucuronides could be detected. The amino-ketones contain one asymmetric carbon atom, but after metabolic reduction a second asymmetric centre is created; little is known of the stereochemistry of the derived amino-alcohols IVY V and VI excreted by man. Hossie (1970) showed that the ratio VI threo: VI erythro compound was approximatively 3:1, but g.1.c. conditions did not give a suitable separation of the diastereoisomers to allow full quantitative assessment. Banci, Cartoni & others (1971) found IV to be present only in the threo form, the V erythro form to be possibly present with V threo form, and VI to be composed of more threo than erythro forms.We have investigated in man the quantitative aspects of the excretion of I and its metabolites I1 to VI, and the stereochemical characteristics of the excreted aminoalcohols IV, V and VI.

Determination of the metabolites of the new designer drugs bk-MBDB and bk-MDEA in human urine

“…Brenneisen et al reported that cathinone is rapidly reduced in vivo to norephedrine, and to lesser extent, norpseudoephedrine [12,13]. Testa also reported that diethylpropion is reduced to aminopro- panols with the creation of a second asymmetric center to some extent [10]. The cause of the difference in the b-ketone reduction pathway among methylone and bk-MBDB (or bk-MDEA) could not be clarified in the present study.…”

“…However, we previously reported the metabolism of methylone in human and rats [5]. In addition, the metabolic pathways of other b-ketoamphetamines including cathinone and methcathinone in humans have been reported [10][11][12][13][14][15]. These reports suggest that Ndealkylation, demethylenation followed by O-methylation, and reduction of the b-ketone moiety could be the possible metabolic pathways of both bk-MBDB and bk-MDEA in humans.…”

Recently abused β-keto derivatives of 3,4-methylenedioxyphenylalkylamines: a review of their metabolisms and toxicological analysis

“…b-Keto-amphetamines, such as cathinone and methcathinone, are known to be metabolized partly by reduction of the ketone group to the corresponding amino alcohols, which are similar compounds to norephedrine and ephedrine, in humans [20][21][22][23][24], and bk-MDPAs are likely partially metabolized by reduction of the b-ketone group (Fig. 1).…”

Pharmacogenetics of amfepramone in healthy Mexican subjects reveals potential markers for tailoring pharmacotherapy of obesity: results of a randomised trial

“…To the best of our knowledge, this is the first report on different AFP metabolizer types. In 1973, Testa and Beckett reported minor intersubject variations under standardized conditions of AFP metabolism; however, their trials were performed on only four subjects 36 . During the clinical trial and at the end, no volunteers showed any adverse effects.…”