The relation between blood levels and urinary excretion of amphetamine under controlled acidic and under fluctuating urinary pH values using [14C]amphetamine

Beckett, A. H.; Salmon, J.; Mitchard, M.

doi:10.1111/j.2042-7158.1969.tb08241.x

Cited by 76 publications

(18 citation statements)

References 4 publications

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“…Under these conditions, the excretion rates of the drug and its basic metabolites are proportional to their plasma concentrations (Beckett, 1966;Beckett, Salmon & Mitchard, 1969;Khan, 1972;Beckett & Khan, to be published).…”

Section: R E S U L T S a N D Discussionmentioning

confidence: 99%

Metabolism and excretion of diethylpropion in man under acidic urine conditions

Testa

Beckett

1973

Journal of Pharmacy and Pharmacology

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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.

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Section: R E S U L T S a N D Discussionmentioning

confidence: 99%

Metabolism and excretion of diethylpropion in man under acidic urine conditions

Testa

Beckett

1973

Journal of Pharmacy and Pharmacology

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“…For calculations of blood level curves, it was assumed that at the measured pH values of urine between 5.0-6.0 (Tables I and II), the amount of the drug excreted in urine reflects the concentration of the drug in blood (Fig. 2) (13,21).…”

Section: Resultsmentioning

confidence: 99%

Urinary excretion and metabolism of orally administered mefenorex

Rendić

Slavica

Medić-Šarič

1994

Eur. J. Drug Metab. Pharmacokinet.

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Metabolic pathways and the pharmacokinetic profile of mefenorex «±)N-(3-chloropropyl)-1-methyl-2-phenylethylamine), and its main metabolite amphetamine (l-methyl-2-phenylethylamine) have been studied in two healthy volunteers, after a single oral dose of mefenorex (1.2 mglkg body weight for a male subject and 2.4 mglkg body weight for a female subject). Urinary concentrations were determined by gas chromatography (GC) and metabolite structure was identified by GCJMS following derivatization of urine extracts. The ratio of this metabolite to unchanged drug in urine samples, collected up to 5 h following administration, was essentially the same after either of the administered doses.The calculated KeI for mefenorex after the higher dose was in the range of 0.191-0.272 h-I, with a biological half life (tm) of 3.98-2.55 h, depending on the method of calculation used. The elimination of amphetamine was much slower with a Kel ranging from 0.039-0.073 h-I and a tIn from 9.5-17.8 h. Depending on the dose administered, the rate constant of metabolite formation was 0.129 and 0.685 h-I for low and high doses, respectively.Urinary excretion of Rondimen S amounted to 11.9% within 72 h after administration. Of this amount, 1.5% represented unchanged drug and 10.4% represented metabolites. In addition to amphetamine 3 other metabolites were identified: p-hydroxy mefenorex, p-hydroxy amphetamine and p-hydroxy-m-methoxy mefenorex.

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“…Under these conditions, the excretion rates of an amine drug and its basic metabolites are proportional to their plasma concentration (Beckett, 1966;Beckett, Salmon & Mitchard, 1969). Under acidic urine control, the above subject excreted 96% of the administered dose of chlorphentermine within 36 h (Table 3).…”

Section: Discussionmentioning

confidence: 99%

The metabolism, distribution and elimination of chlorphentermine in man.

Beckett¹,

Belanger²

1977

Brit J Clinical Pharma

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I A gas-liquid chromatography procedure for the determination of chlorphentermine (I), N-hydroxychlorphentermine (II) and a,o-dimethyl-a-nitro-,-44-chlorophenyl)ethane (IV) in urine has been developed. Also methods are reported to determine conjugated II and the total N-oxidized metabolites of I, i.e. II, conjugated II, a,a-dimethyl-a-nitroso-3-(4-chlorophenyl)ethane (III) and IV in urine.2 The synthesis of ,ct-dimethyl-a-nitroso-f-(4-chlorophenyl)ethane (III) and its properties are reported. 3 The kinetics of urinary excretion of I and its metabolic products after the oral administration of I to a human subject on separate occasions have been studied. Under normal conditions of urinary pH, metabolism by N-oxidation was the main elimination route of I; acidifying the urine increased the urinary excretion of unchanged I at the expense of the N-oxidized products. 4 The importance of the N-oxidation metabolic route in the distribution of chlorphentermine (I) in man is discussed.

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The relation between blood levels and urinary excretion of amphetamine under controlled acidic and under fluctuating urinary pH values using [14C]amphetamine

Abstract: The relation between blood levels and urinary excretion of amphetamine under controlled acidic and under fluctuating urinary pH values using [ 14C]amphetamine

Cited by 76 publications

References 4 publications

Metabolism and excretion of diethylpropion in man under acidic urine conditions

Metabolism and excretion of diethylpropion in man under acidic urine conditions

Urinary excretion and metabolism of orally administered mefenorex

The metabolism, distribution and elimination of chlorphentermine in man.

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