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Metabolism of [IC ]Methamphetamine in Man, the Guinea Pig and the Rat

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Metabolism of [IC ]Methamphetamine in Man, the Guinea Pig and the Rat Biochem. J. (1972) 129, 11-22 11 Printed in Great Britain Metabolism of [IC ]Methamphetamine in Man, the Guinea Pig and the Rat By J. CALDWELL, L. G. DRING and R. T. WILLIAMS Department of Biochemistry, St. Mary's Hospital Medical School, London W.2, U.K. (Received 2 March 1972) 1. The metabolites of (±)-2-methylamino-1-phenyl[1-14C]propane ([14C]methamphet- amine) in urine were examined in man, rat and guinea pig. 2. In two male human subjects receiving the drug orally (20mg per person) about 90% ofthe 14C was excreted in the urine in 4 days. The urine ofthe first day was examined for metabolites, and the main metabolites were the unchanged drug (22% of the dose) and 4-hydroxymethamphetamine (15 %). Minor metabolites were hippuric acid, norephedrine, 4-hydroxyamphetamine, 4-hydroxy- norephedrine and an acid-labile precursor of benzyl methyl ketone. 3. In the rat some 82 % of the dose of '4C (45mg/kg) was excreted in the urine and 2-3 % in the faeces in 3-4 days. In 2 days the main metabolites in the urine were 4-hydroxymethamphetamine (31 % ofdose), 4-hydroxynorephedrine (16 %) and unchanged drug (11 %). Minor metabo- lites were amphetamine, 4-hydroxyamphetamine and benzoic acid. 4. The guinea pig was injected intraperitoneally with the drug at two doses, 10 and 45mg/kg. In both cases nearly 90% of the 14C was excreted, mainly in the urine after the lower dose, but in the urine (69%) and faeces (18%) after the higher dose. The main metabolites in the guinea pig were benzoic acid and its conjugates. Minor metabolites were unchanged drug, amphetamine, norephedrine, an acid-labile precursor of benzyl methyl ketone and an unknown weakly acidic metabolite. The output of norephedrine was dose-dependent, being about 19 % on the higher dose and about 1 % on the lower dose. 5. Marked species differences in the metabolism of methamphetamine were observed. The main reaction in the rat was aromatic hydroxylation, in the guinea pig demethylation and deamination, whereas in man much of the drug, possibly one-half, was excreted unchanged. Methamphetamine (2-methylamino-1-phenylprop- hydroxylation and demethylation are significant re- ane) is regarded as dangerous from the point of view actions. All three species also excrete norephedrine of drug dependence and its use has been restricted derivatives after dosage with the drug, the rat produc- since 1968 to hospitals for therapeutic purposes ing 4-hydroxynorephedrine [2-amino-1-(4'-hydroxy- (Editorial, 1968). However, little work has been done phenyl)propan-l-ol], the guinea pig, norephedrine on its metabolism. Richter (1938) reported that it was (2-amino-1-phenylpropan-1-ol), and man, both. excreted unchanged by man, but more recently Norephedrine and its 4-hydroxy derivative have been Cartoni & de Stefano (1963) and Beckett & Rowland implicated as false transmitters at nerve endings and (1965) have shown that it is excreted partly un- may be involved in the undesirable effects of the changed and partly as amphetamine (2-amino-i- chronic intake of the amphetamines (see Brodie et al., phenylpropane). In the dog, Axelrod (1954) found 1970). Evidence is also produced that in the guinea that it was largely demethylated to amphetamine and pig at least, the production of norephedrine is dose- converted to some extent into 4-hydroxyamphet- dependent. Part of the work has been briefly reported amine [2-amino-1-(4'-hydroxyphenyl)propane]. (Caldwell et al., 1971). In the present paper we show that in the rat and guinea pig, (±)-methamphetamine is extensively Materials and Methods metabolized and that there are marked differences between these two species in the way in which they Compounds metabolize the drug. In the rat the main metabolic reaction is aromatic hydroxylation, as was found to (±)-Amphetamine sulphate, m.p. 302°C (decomp.), be the case with amphetamine (Dring et al., 1970), (±)-4-hydroxyamphetamine hydrobromide (Pared- whereas in the guinea pig the main reaction is de- rine), m.p. 190-1920C, and (±)-norephedrine hydro- methylation followed by side-chain degradation. In chloride, m.p. 190-1940C, were gifts from Smith, man, much more of the drug is excreted unchanged Kline and French Laboratories, Philadelphia, Pa., than in the rat and guinea pig, but both aromatic U.S.A. (±)-4-Hydroxymethamphetamine sulphate, Vol. 129 12 J. CALDWELL, L. G. DRING AND R. T. WILLIAMS m.p. 296°C (decomp.), was the gift from Knoll A.G., hydrochloride in water was administered to rats by Ludwigshafen-am-Rhein, West Germany; (±)-meth- stomach tube or intraperitoneal injection and to amphetamine hydrochloride, m.p. 132-134°C, was guinea pigs by intraperitoneal injection. All doses are purchased from K & K Laboratories, Plainview, expressed as methamphetamine hydrochloride, which N.Y., U.S.A.; (±)-4-hydroxyephedrine hydro- contains 80% of methamphetamine. The animals chloride, m.p. 188-189°C, was from R. N. Emanuel, were kept singly in suitable metabolism cages and Wembley, Middx., U.K. (±)-4-Hydroxynorephedrine urine and faeces were collected daily. was a sample prepared by Dring et al. (1970). The other known compounds used were purchased and Radiochemical techniques suitably purified. Synthesis of [14C]methamphetamine [(±)-2-methyl- The 14C in urine and faeces was determined as amino-l-phenyl[1-_4Cjpropane]. [carboxy-14C]Ben- described by Bridges et al. (1967) with the Packard zoic acid (m.p. 121°C; 3.6,uCi/mg) was prepared Tri-Carb liquid-scintillation spectrometers (models from Ba14CO3 (The Radiochemical Centre, Amer- 3214, 3320 and 3375). Scans of paper and thin-layer sham, Bucks., U.K.) as described by Dauben et al. chromatograms were made with a Packard radio- (1947). This was converted into [carbonyl-'4C]benzoyl chromatogram scanner (model 7200), and identifica- chloride as described by Calvin et al. (1949). The tions of 14C peaks were made by comparison with chloride (2.08g) was added drop by drop to NH3 authentic compounds (see Table 1). The 14C was (sp.gr. 0.88; 10ml) cooled in ice. The [carbonyl-'4C]- measured from the chromatogram scans and also by benzamide which separated was recrystallized from cutting paper chromatograms into 1 cm segments and water (yield 1.42g; m.p. 129°C). The amide was inti- counting the radioactivity of these with scintillator mately mixed with phosphorus pentoxide (3g) and fluid in the scintillation counter. With t.l.c. plates, heated under reduced pressure, whereby benzo['4C]- 0.5cm-wide sections of the absorbent were scraped nitrile (0.88g) distilled at 162°C/20mmHg and was into scintillation vials, scintillator fluid was added and converted into [carbonyl-14C]benzaldehyde (0.77g) the radioactivity was then counted in the spectro- by the method of Stephen (1925). The aldehyde in meter. benzene (lOml) was treated with nitroethane (4ml) as Guinea-pig faeces were homogenized with 2vol. of described by Blackburn & Burghard (1965) to give water in a Waring Blendor. The homogenate (20ml) 2-nitro-1-phenyl[1-4C]prop-l-ene (0.89g) as an oil, was made alkaline with 10M-NaOH and an equal which was converted without further purification volume of H202 solution (100vol) added with a few into I-phenyl[1-14C]propan-2-one (0.34g) by the drops of 2-ethylhexanol to control foaming. The general method of Pearl & Beyer (1951). mixture was kept at room temperature for 3 days The phenylpropan-2-one in ethanol (30ml) and an until decolorized, and was then assayed for 14C by ethanolic solution of methylamine (20ml; 33 %, w/w) scintillation counting for radioactivity. The un- was placed in the reaction vessel of a hydrogenator. bleached homogenate was centrifuged and the radio- Palladium-charcoal (10%; 2g) was added and the active compounds present in the supernatant were mixture hydrogenated at 310kN/m2 (451bf/in2) for separated by paper chromatography and t.l.c. and 24h. The catalyst was filtered, and excess of methyl- determined as described above. amine and ethanol were removed from the filtrate by Isotope-dilution procedures distillation in vacuo. The residual oil was then treated with a dry saturated ethereal solution (5ml) of HCI Amphetamine, 4-hydroxyamphetamine, benzyl gas. White crystals (0.42g) of (±)-2-methylamino- methyl ketone (1-phenylpropan-2-one), 4-hydroxy- 1-phenyl[1-14C]propane hydrochloride separated on norephedrine, hippuric acid, benzoic acid and 4- standing. It had m.p. 134-1350C and specific radio- hydroxybenzoic acid were assayed as described by activity 2.36,uCi/mg [Woodruff et al. (1940) give the Dring et al. (1970). About one-tenth of the urine m.p. of (±)methamphetamine hydrochloride as collected was used for the isotope dilutions described 135-136°C]. On chromatography in solvents A, B below. and C (see Table 1) it showed a single spot of RF 0.56, Methamphetamine. (+)-Methamphetamine hydro- 0.93 and 0.80 respectively. The radiochemical yield chloride (1 g) was dissolved in the urine and the solu- based on the Ba14CO3 used initially was 10%, and the tion adjusted to pH 14 with 1OM-NaOH. The solution radiochemical purity was >99 %, as measured by was extracted with diethyl ether (3 x 100ml), the ex- isotope dilution with the tosyl derivative (see below). tract was dried (with anhydrous Na2SO4) and evapor- ated to dryness and the residue was dissolved in Animals 2.5M-NaOH (20ml). Toluene-p-sulphonyl chloride (1.75g) in acetone (6ml) was added and the mixture Female Wistar albino rats weighing 220+15g and boiled under reflux for 20min. The solution was female Duncan-Hartley albino guinea pigs weighing poured on ice (lOg) and the solid toluenesulphonyl 250± 15g were used. The (±)-[L14Cjmethamphetamine derivative filtered and recrystallized from aq. 1972 SPECIES VARIATIONS IN METHAMPHETAMINE METABOLISM 13 ethanol to constant specific radioactivity.
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