Metabolism amphetamines

Green, C.E., LeValley, S.E. and Tyson, C.A. (1986). Comparison of amphetamine metabolism using isolated hepatocytes from five species including human. J. Pharm. Exp. Ther. 237 931-936. 

Kraemer T and Maurer HH (2002) Toxicokinetics of amphetamines Metabolism and toxicokinetic data of designer dmgs, amphetamine, methamphetamine and their N-alkyl derivatives. Therapeutic Drug Monitoring 24(2) in-im. 

Anggard E, Jonsson L-E, Hc jnark A-L, Gurme L-M Amphetamine metabolism in amphetamine psychosis. Clin Pharmacol Ther( 9TS) 14,870-80. 

The symptomatic action of MAO-B inhibitors is mediated by blockade of the MAO-B enzyme involved in dopamine degradation, which results in increased dopamine availability at the synapse. This is not, however, the only mechanism of action. The symptomatic effect is also mediated by inhibition of amine uptake and a major increase in phenylethylamine concentrations in the striatum. Phenylethylamine is a trace amine which can amplify dopaminergic transmission. In addition, it has been proposed that blocking MAO-B metabolism of N-acetylated polyamine derivatives could modulate the activity of inhibitor glutamatergic efferents at the subthalamic level. The exact role of selegiline in amphetamine metabolism is not clearly understood. 

Axelrod, J., 1970, Amphetamine Metabolism, physiological disposition and its effects on catecholamine storage, in International Symposium on Amphetamines and Related Compounds (Proc. Mario Negri Institute for Pharmacological Research, Milan, Italy), Raven Press, New York. 

Kraemer, T., and H. H. Maurer. 2002 Toxicokinetics of amphetamines metabolism and tox-icokinetic. Data of designer drugs, amphetamine, methamphetamine, and their N-alkyl derivatives. Therapeut DrugMonit 24 277-289. 

Several classes of drugs modulate the firing rates or patterns of midbrain dopamine neurons by direct, monosynaptic, or indirect, polysynaptic, inputs to the cell bodies within the ventral mesencephalon (i.e., nicotine and opiates). In contrast, amphetamine, cocaine, and methylphenidate act at the level of the dopamine terminal interfering with normal processes of transmitter packaging, release, reuptake, and metabolism. 

Amantidine, bromocriptine, mazindol, pergolide, cabergoline, L-dopa/carbidopa, pramipexole, ABT-431, catecholamine metabolism inhibitors (disulfiram, phenelzine, selegiline), amineptine Methylphenidate, /-amphetamine, tropanes, GBR-12909 (partial agonist that may also act as antagonist), modafinil, coca tea... 

The removal of released DA from the synaptic extracellular space to facilitate its intraneuronal metabolism is achieved by a membrane transporter that controls the synaptic concentration. This transporter has been shown to be a 619 amino-acid protein with 12 hydrophobic membrane spanning domains (see Giros and Caron 1993). Although it has similar amino-acid sequences to that of the NA (and GABA) transporter, there are sufficient differences for it to show some specificity. Thus DA terminals will not concentrate NA and the DA transporter is blocked by a drug such as nomifensine which has less effect on NA uptake. Despite this selectivity some compounds, e.g. amphetamine and 6-OHDA (but not MPTP), can be taken up by both neurons. The role of blocking DA uptake in the central actions of cocaine and amphetamine is considered later (Chapter 23). 

Cocaine, a stimulant, blocks the reuptake of NA (and DA) and so has similar actions to those of the amphetamines which have a number of actions that include the release of NA and DA, and a block of reuptake and metabolism. 

COMMENT/QUESTION I was not using MDMA-like in the sense that you were using it—as a substitute. I am simply saying it did not have the pharmacologic effect that MDMA had namely, substitution for amphetamine, which obviously must mean that the N-hydroxy compound is not converted to MDMA to the same extent at least as the p-toluylamphetamine analog was. I would like to know if you have any information about the metabolism of those N-hydroxy compounds. 

Caldwell, J. The metabolism of amphetamines and related stimulants in animals and man. In Caldwell, I, ed. Amphetamines and Related Stimulants Chemical, Biological, Clinical, and Sociological Aspects. 

Dyn is not yet known, it is likely that such changes reflect variations in the activity of the associated pathways. One possible explanation is that increases in neuropeptide tissue levels are due to decreased release of the transmitter, which dunmishes the extracellular peptide metabolism and results in accumulation of these peptide substances. Another possible contributing factor is a drug-related alteration in neuropeptide synthesis. For example, Bannon et al. (1987) reported that METH administration increased the quantity of striatal messenger RNA for the SP precursor preprotachykinin. Thus, increases in peptide synthesis might contribute to increases in peptide content caused by treatment with METH or the other amphetamine analogs. 

Caldwell, J. The metabolism of amphetamines in mammals. Drug Metab Rev 5 219-280, 1976. 

The neurotoxic effects of all these compounds are antagonized by inhibitors of monoamine uptake (table 1), implicating the membrane uptake carrier on serotonin and dopamine neurons in the mechanism of neurotoxicity. In this regard, these amphetamines are like a drug somewhat related in structure, namely l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP), a Parkinsonism-causing neurotoxic dmg that has been studied intensely since 1983 (Langston and Irwin 1986). In the case of MPTP, the mechanism by which inhibitors of the dopamine uptake carrier block the neurotoxicity toward dopamine neurons (mainly nigrostriatal dopamine neurons) seems clear. A metabolite of MPTP, l-methyl-4-phenylpyridinium (MPP-I-), has been shown to be a substrate for the dopamine uptake carrier (Javitch et al. 1985). Thus accumulation of MPP-I-, formed metabolically from... 

Isolated seizures that are not epilepsy can be caused by stroke, central nervous system trauma, central nervous system infections, metabolic disturbances (e.g., hyponatremia and hypoglycemia), and hypoxia. If these underlying causes of seizures are not corrected, they may lead to the development of recurrent seizures I or epilepsy. Medications can also cause seizures. Some drugs that are commonly associated with seizures include tramadol, bupropion, theophylline, some antidepressants, some antipsy-chotics, amphetamines, cocaine, imipenem, lithium, excessive doses of penicillins or cephalosporins, and sympathomimetics or stimulants. 

The consumption indicator is the metabolic byproduct excreted at the highest rate. It may be a metabolite, as it is the case for cocaine (BE) and heroin (MOR), or the drug itself, as it is the case of amphetamine-like compounds. THC, the most psychoactive cannabinoid of the cannabis herb, is highly metabolized before excretion, thus, the consumption indicator selected (THC-COOH) presents an excretion rate of 0.6%. Despite the fact that OH-THC presents a slightly higher excretion rate (2%), this analyte was not selected to back calculate cannabis use due... 

Trulson, M. E., and Jacobs, B. L. (1979) Long-term amphetamine treatment decreases brain serotonin metabolism Implications for theories of schizophrenia. Science, 205 1295-1297. 

While mescaline is a simple 2-phenethylamine derivative, the addition of an alpha-methyl group to the side chain yields Structure 8 (TMA). This simple hybrid of the structures of mescaline and amphetamine retains the hallucinogenic effects of mescaline but possesses about twice the potency of the latter (174,200). Addition of the alpha-methyl to other 3,4,5-substituted compounds generally brings about an approximately twofold increase in potency. The addition of an alpha-methyl to 2,4,5-substituted compounds, however, may dramatically increase activity. For example, 2-(2,4,5-trimethoxyphenyl) ethylamine apparently is clinically inactive (195). Addition of an alpha-methyl gives TMA-2 (Table 1), with 20 times the potency of mescaline. However, the addition of an alpha-methyl does not significantly increase in vitro receptor affinity in either 3,4,5-or 2,4,5-series (72,78). Thus it is probable that the alpha-methyl may confer metabolic stability in vivo. It could also be speculated that this protection is more important in the 2,4,5-substituted series than in 3,4,5-substituted compounds. 

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