L. G. Dring

The fate of amphetamine in man and other mammals

SrR,-Axelrod (1954a,b; 1955) showed that amphetamine (I) could be metabolised along two routes ; by aromatic hydroxylation to p-hydroxyamphetamine (11) and by deamination to benzyl methyl ketone (111). This ketone could then yield 1-phenylpropan-2-01 (IV) in vivo, and it has been shown in this laboratory (Smith, Smithies & Williams, 1954; El Masry, Smith & Williams, 1956) that it is, in fact, metabolised to (+)-l-phenylpropan-2-01 and benzoic acid, whilst the alcohol is partly oxidised to benzoic acid (V) and partly conjugated with glucuronic acid. The main pathways of amphetamine metabolism (excluding conjugation) could be expressed in this scheme. C H . CH, . CH . CH, -4 C,H,. CH, . C . CH, -+ C,H, . CH, . CO . CH, IJ (1) AH2 /I

The metabolism of (-)-ephedrine in man.

SummaryThe metabolic fate of orally administered (−)-[14C]-ephedrine has been studied in 3 human subjects and the urinary excretion of metabolites determined quantitatively by solvent extraction, paper chromatography and reverse isotope dilution procedures. Following an oral dose of the drug (0.35 mg/kg, 1.6 µCi), 97% of the dose was excreted in the urine within 48 h, 88% in the first 24 h. Unchanged drug was the major urinary excretory product (53–74%), with N-demethylation occurring to a variable extent (8–20%) although there was little interindividual variation in urine pH. Oxidative deamination was also variable (4–13%); the main identified products of this were benzoic acid (free and conjugated) and 1,2-dihydroxy-1-phenylpropane (free and conjugated). No phenolic metabolites could be detected, and thus it would appear that these compounds cannot be implicated in the acquisition of tolerance to ephedrine which can occur on repeated dosage.

The metabolism of amphetamine in dependent subjects.

SummaryThe metabolism of (+)-[14C] amphetamine has been studied in two women who had been taking 90–100 mg of Dexedrine ((+)amphetamine sulphate; Smith, Kline & French) daily for several years but who showed no evidence of overt amphetamine toxicity. The urinary metabolites were identified, estimated and compared with the results previously obtained from two drug naive male subjects who had received 20 mg of (±)amphetamine (Caldwellet al., (1972b). The same metabolites were found, but the dependent subjects excreted in 24 h more unchanged amphetamine (about 30% of dose) than the naive subjects (20%). This may be a reflection of the dose, which in dependent subjects was five times that of naive subjects. The dependent subjects excreted in 24 h slightly more norephedrine (2.9, 4.1% of dose) and 4′-hydroxynorephedrine (1.1, 1.6%) than the naive subjects (norephedrine, 2.2, 2.6%; 4′-hydroxynorephedrine, 0.3, 0.4%), but the difference in percentage of dose may not be significant. However, in absolute terms the dependent subjects are producing at least five times as much norephedrines as the naive subjects because of the larger dose.

Comparative metabolism of some amphetamines in various species

Publisher Summary This chapter elaborates the comparative metabolism of some amphetamines in various species. The β-hydroxylation of the benzene ring of the amphetamines is a reaction which occurs extensively and consistently in the rat but not to any great extent in the other species. Three drugs have been examined for this reaction in various species, namely methamphetamine, ephedrine and mephentermine, which contain an N-methyl group. It is suggested that β-hydroxylation is a relatively minor metabolic reaction of the amphetamines. In the guinea pig, and rat, β-hydroxylation occurs more extensively with methamphetamine than with amphetamine, and paredrine. The values of 16% of the dose in the rat, and 19% in the guinea pig are for doses of methamphetamine of 45 mg/kg, whereas the 1% quoted for the guinea pig was obtained with 10 mg/kg. This might suggest that in the guinea pig the production of norephedrine is dose dependent. In normal humans α-hydroxylation is about 3–5% but in the amphetamine tolerant human, β-hydroxylation is higher than in normal humans.