Methamphetamine metabolism

Bakhit, C. Morgan, M.E. Peat, M.A. and Gibb. J.W. Long-term effects of methamphetamine on the synthesis and metabolism of 5-hydroxytryptamine in various regions of the rat brain. Neuropharmacology 20 1135-1140, 1981. 

Morgan, M.E., Gibb, J.W. Short-term and long-term effects of methamphetamine on biogenic amine metabolism in extra-striatal dopaminergic nuclei. Neumpharmacology. 19 989, 1980. 

Kitanaka, N., Kitanaka, J., Takemura, M. Behavioral sensitization and alteration in monoamine metabolism in mice after single versus repeated methamphetamine administration. Eur. J. Pharmacol. 474 63, 2003. 

Volkow, N.D., Chang, L., Wang, GJ. et al. Higher cortical and lower subcortical metabolism in detoxified methamphetamine abusers. Am. J. Psychiatry. 158 383, 2001. 

London, E.D., Simon, S.L., Berman, S.M. et al. Mood disturbances and regional cerebral metabolic abnormalities in recently abstinent methamphetamine abusers. Arch. Gen. Psychiatry. 61 73, 2004. 

FIGURE 4.27 FMO-catalyzed oxidation of amphetamine and methamphetamine and the structures of their metabolic products. 

A final pharmacological strategy for treatment of Parkinson s disease comes from enzyme inhibition. This was initally done with an MAO inhibitor, L-deprenyl (selegiline, Eldepryl), but more recent drugs have become available that are COMT inhibitors. L-Deprenyl is an inhibitor of MAOB, which is the form of MAO selective to dopamine. Thus, it may increase the amount of available dopamine for release. Second, it may protect dopamine neurons by reducing the oxidative stress concomitant with dopamine metabolism (Olanow 1997). Third, L-deprenyl is metabolized into amphetamine and methamphetamine, which may contribute to their antiparkinsonian effects. Unlike other treatments for Parkinson s disease, L-deprenyl seems to slow the progression of the disease. Tolcapone (Tasmar) is a COMT inhibitor, which prevents extracellular breakdown of dopamine. 

CNS stimulants can be classified as Psychomotor stimulants compounds that display a stimulatory effect primarily on brain functions and which activate mental and physical activity of the organism. They are made up of methylxanthines (caffeine, theophylline, pentoxifyllin), amphetamines (dextroamphetamine, methamphetamine), and also methylphenidate and pemoline. Respiratory stimulants or analeptics compounds, which cause certain activations of mental and physical activity of the organism, and primarily excite the vasomotor and respiratory centers of the medulla (doxapram, almitrine).Drwgi that suppress appetite or anorectics drags that activate mental and physical activity of the organism, but primarily accentuate the excitatory center of satiation in the hypothalamus (phentermine, diethylpropion).In order to increase mental capability, nootropics — drugs that increase the functional state of the brain — are sometimes used, the effect of which is associated with blood flow and metabolism of the brain. 

Methamphetamine - Methamphetamine is rapidly absorbed from the Gl tract. The primary site of metabolism is in the liver. The biological half-life is in the range of 4 to 5 hours. Excretion occurs in the urine and is dependent on urine pH. Alkaline urine increases the drug half-life. 

Pharmacokinetics Rapidly absorbed from the G1 tract. Crosses the blood-brain barrier. Metabolized in the liver to the active metabolites. Primarily excreted in urine. Half-life 17hr (amphetamine), 20 hr (methamphetamine). 

Methamphetamine passes the blood-brain barrier better than amphetamine, and there is evidence that chronic use of methamphetamine can result in permanent damage to dopamine neurons. Both pass the placental barrier, and there is some evidence that abuse by a pregnant woman can result in fetal abnormalities. Methamphetamine is found in breast milk. The half-life of methamphetamine and amphetamine is about 10 to 13 hours. Some methamphetamine is metabolized to amphetamine, and amphetamine-glucuronide can be detected in urine for about two days. About 50% of methamphetamine is excreted unchanged in the urine over two to three days. 

Cathinone is metabolized to norephedrine and norpseudo-ephedrine. Cathinone is found in breast milk. Babies of mothers who used khat have low birth weights. Methcathinone acts like methamphetamine, and effects last four to six hours. 

A positive screening test result for amphetamines may be due to use of amphetamine or methamphetamine-containing prescription or over-the-counter drugs. For example, the drug Selegiline, which is used to treat Parkinson s disease, is metabolized to amphetamine and methamphetamine. The nasal decongestant pseudoephedrine can cross-react in the test and result in a false positive. In the latter case, the confirmatory test is for amphetamine. 

Stimulant drugs commonly abused in the USA include methamphetamine ("crank," "crystal"), methylenedioxymethamphetamine (MDMA, "ecstasy"), and cocaine ("crack") as well as pharmaceuticals such as pseudoephedrine (Sudafed) and ephedrine (as such and in the herbal agent Ma-huang) (see Chapter 32). Caffeine is often added to dietary supplements sold as "metabolic enhancers" or "fat-burners" and is also sometimes combined with pseudoephedrine in underground pills sold as amphetamine substitutes. 

A third pathway for oxime formation is given by tautomerization of nitroso compounds possessing an a-hydrogen (equation 9). Such a process involves an intramolecular redox reaction, in which the nitrogen undergoes a formal two-electron reduction, while the a-carbon is oxidized. Kinetic analysis of this conversion, as performed with a set of a-substituted 2-nitroso-l-phenylethane compounds, has revealed sensitivity toward both the bulkiness of the substituents and the initial concentration of the nitroso dimers128. For instance, tautomerization of 2-nitroso-l-phenylpropane to 28 has been proposed to play a role in the metabolism of methamphetamine by fortified rat liver tissue129. 

Moreover, nitrones can be generated from N-hydroxy products during extraction into an organic solvent, such as diethyl ether. The latter contains acetaldehyde as an impurity even after careful distillation. Indeed, nitrones arising as artifacts from the reaction of primary hydroxylamines, metabolically derived from methamphetamine and chlorpromazine, with acetaldehyde upon sample treatment with ether have been identified23,39. Acetone is frequently used as one of the components of the solvent systems applied for TLC analysis. 

Volkow, N., L. Chang, G. Wang, et al. Higher Cortical and Lower Subcortical Metabolism in Detoxified Methamphetamine Abusers. The American Journal of Psychiatry 3 (March 2001) 383-389. 

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