P-hydroxyamphetamine

Soares ME, Carvalho F, Bastos ML. 2001. Determination of amphetamine and its metabolite p-hydroxyamphetamine in rat urine by reversed-phase high-performance liquid chromatography after dabsyl derivatization. Biomed Chromatogr 15(7) 452-426. 

The metabolism of amphetamine has been studied in those presenting with amphetamine psychosis. In the presence of acidified urine, the renal elimination of amphetamine increased significantly. The intensity of the psychosis was found to correlate with the amount of basic polar metabolites excreted in the urine, such as norephedrine and p-hydroxyamphetamine, and not with the plasma amphetamine concentration. This suggests that these metabolites may play an important role in the development of paranoid psychosis in chronic amphetamine users.6... 

Amphetamines and Phenethylamines. Deficiency in the p-hydroxylation of amphetamine was one of the observations that led to the discovery of the CYP2D6 polymorphism (Bring et al. 1970 Smith 1986). A single oral administration of the radiolabelled enantiomers of amphetamine to three volunteers with subsequent analysis of urine indicated that about 5 percent of (+)-amphetamine was converted to p-hydroxyamphetamine in two subjects but to a much less extent in the third subject, who was later found to have CYP2D6 deficiency (Smith 1986). The main excretion product was unchanged amphetamine (although the extent of excretion is known to be pH dependent), and the major metabolites were products of side... 

Urinary excretion data of human subjects indicate that 4-hydroxylation of methamphetamine is much more extensive than that of amphetamine the metabolic ratio (total hydroxymethamphetamine/methamphetamine) in urine averaged about 15 with individual variations of approximately fiftyfold (Shimosato 1988), suggesting considerable importance of CYP2D6 polymorphism in the fate of methamphetamine. On the other hand, there seems to be no information on the further metabolism of p-hydroxymethamphetamine as is available for p-hydroxyamphetamine. 

Suzuki and colleagues (1986, 1987) have tested the effects of altering methamphetamine p-hydroxylation in rats it appeared that inhibition enhanced the methamphetamine-induced stereotyped behavior. One might conjecture that an equivalent effect could occur in humans with inborn CYP2D6 deficiency if a toxic dose of methamphetamine were applied. Unfortunately, studies of animals do not necessarily help p-hydroxyamphetamine is the main metabolite of amphetamine in rats but not in human liver (see above), and most studies on brain metabolism have not been conducted in human tissue. 

Aral, Y. Kim, S.Y. Kinemuchi, H. Tadano, T. Satoh, S. and Satoh, N. Inhibition of brain type A monoamine oxidase and 5-hydroxytryptamine uptake by two amphetamine metabolites, p-hydroxyamphetamine and p-hydroxynorephedrine. JNeurochem 55 403-408, 1990. 

Hoffman, A.R. Rama-Sastry, B.V. and Axelrod, J. Formation of alpha- methyldopamine ("catecholamphetamine") from p-hydroxyamphetamine by rat brain microsomes. Pharmacology 19 256-260, 1979. 

K. Ishikawa, J.L. Martinez and J.L. McGaugh, Simple determination of p-hydroxyamphetamine by high-performance liquid chromatography with electrochemical detection, J. Chromatogr., 1984, 306, 394-397. 

Hydroquinone (C6H6O2) p-Hydroxy-y-aminobutyric acid (C4H9NO3) N-hydroxyamphetamine (C9H13NO) 4-Hydroxyamphetamine (Paredrine) (C9H13NO)... 

After consumption of p-methoxyamphetamine (PMA), more than 80% of the amount of substance taken is excreted within a day via the urine, up to 15% unchanged, >25% in the form of the free 4-hydroxyamphetamine, and ca. 50% as conjugated 4-hydroxyamphetamine. The remainder, in analogy to amphetamine, is further metabolized [44]. In analogy to PMA, TMA undergoes a demethylation to form mono- and di-O-desmethyl derivatives. In methoxyamphetamines, two methoxy groups are located in the para position (DOB, DOM), so that demethylation to hydroquinone is also possible [51]. 

Why more appealing For one thing, oxidative changes are much more common in the body than reductive changes. For another, the conversion of amphetamine to N-hydroxyamphetamine is an intermediate in the conversion of amphetamine to phenylacetone, a known metabolic process in several animal species. And that intermediate, N-hydroxyamphetamine, is a material that gives the famous cytochrome P-450 complex that has fascinated biochemists studying the so-called NADPH-dependent metabolism. 

N-hydroxyamphetamine, is a material that gives the famous cytochrome P-450 complex that has fascinated biochemists studying the so-called NADPH-dependent metabolism. 

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