The interaction of ethanol and amphetamine metabolism

Abstract

Ethanol, 1,3, and 5 g/kg, depresses the hydroxylation of amphetamine by the rat in vivo. At 5 g/kg, ethanol does not affect the hydroxylation of acetanilide or biphenyl in vivo. Amphetamine hydroxylation is unaffected by phenobarbitone or benzo[a]pyrene pretreatment but is depressed by pretreatment with 2-diethylaminoethyl-2,2-diphenylvalerate (SKF 525-A), 2,4-dichloro-6-phenylphenoxyethylamine (DPEA), and 2,4-dichloro-6-phenylphen~xy-NN-dieth~leth~lamine (Lilly 18947).We have reported previously that ethanol treatment markedly inhibits the hydroxylation of amphetamine by the rat in vivo (Creaven & Barbee, 1969). We have now made further investigations of this and other aspects of amphetamine hydroxylation in an attempt to determine the mechanism of this inhibition by ethanol and to elucidate the differences between amphetamine hydroxylation and that of other drugs. E X P E R I M E N T A L Materials and methodsMale Sprague-Dawley rats, 100 to 150 g, received intraperitoneal injections of ( f)-[2-14C]amphetamine sulphate 5 mg/kg (1 -6 mCi/mM), acetanilide (250 mg/kg in isotonic saline) or biphenyl (200 mg/kg in arachis oil). The animals were placed in metabolism cages and urine samples collected in flasks at 0 to 2' . Urinary pH was recorded and the urine frozen.Animals were pretreated with 1, 3, or 5 g/kg ethanol by stomach tube as a 25% solution (v/v) in water 30 min before the administration of amphetamine. Control animals received an equal volume of saline.Benzo[a]pyrene (2 mg/kg) and phenobarbitone (80 mg/kg) were administered intraperitoneally daily for three days; amphetamine was injected 24 h after the final dose. 2-Diethylaminoethyl-2,2-diphenylvalerate hydrochloride (SKF 525-A), 2,4-dichloro-6phenylphenoxyethylamine hydrochloride (DPEA), and 2,4-dichloro-6-phenylphenoxy-NN-diethylethylamine hydrobromide (Lilly 18947), 35 mg/kg, were injected intraperitoneally 45 min before the administration of amphetamine.Pyrazole (100 mg/kg in isotonic saline) and disulfiram (100 mg/kg in arachis oil) were injected intraperitoneally 15 and 30 min, respectively, before oral administration of 3 g/kg of ethanol. Amphetamine was injected 30 min after ethanol administration.Metabolites were identified by two-dimensional paper chromatography of urine to which authentic amphetamine andp-hydroxyamphetamine had been added. Chromatograms were developed in I-butanol-acetic acid-water (4 : 1 : 1 v/v) followed by 2propanol-ammonia-water (8 : 1 : 1 v/v) (Asatoor, Galman & others, 1965).

A Novel and Neurotoxic Tetrahydroisoquinoline Derivative In Vivo: Formation of 1,3‐Dimethyl‐1,2,3,4‐Tetrahydroisoquinoline, a Condensation Product of Amphetamines, in Brains of Rats Under Chronic Ethanol Treatment

“…1,3-DiMeTIQ may be formed by ring cyclization of amphetamines, analogs of phenylethylamine, with acetaldehyde, an oxidized product of ethanol. It is reported that ethanol treatment markedly inhibits the phydroxylation of amphetamine and induces a higher level of amphetamine in rat brain and blood (Creaven and Barbee, 1969;Creaven et al, 1970;Todzy et al, 1978;Shimosato, 1988). The effect of ethanol may cause ring cyclization of amphetamine more readily in vivo.…”

Metabolic Interaction of Ethanol and Alprenolol in Isolated Liver Cells

“…In the numerous studies Concerned with the aspect of metabolic interaction, mostly an inhibitory effect of ethanol on the metabolism of drugs in vivo (SCHUPPEL 1969;CREAVEN et al 1970;THOMAS et al 1972) and in vitro (SCHUPPEL et ul. 1967;RUBIN et al 1970a;PETRUCH & SCHUPPEL 1971) as well as on the metabolism of other foreign compounds (VILLENEUVE & PHIL-LIPS 1971; COHEN & MNERING 1973) has been observed and has been ascribed to a direct inhibitory action of ethanol on the microsomal mixed function oxidation pathway (SCHUPPEL 1969).…”