Primary amine metabolites

In general, dealkylation of secondary amines is believed to occur before oxidative deamination. Some evidence indicate ., however, that this may not always be true. Direct deamination of the secondary amine also has occurred. For uampic. in addition to uncleigoing deamination through its dcsisopropyl primary amine metabolite, propranolol can undergo a direct oxidative deamination reaction (also by a-carbon hydroxylalion) to yield the aldehyde metabolite and Mpropylamine (Fig. 4-9). How much direct oxidative deamination contributes to the metabolism of. secondary amines remains unclear. 

Figure 4-9 Metabolism of propranolol to its aldehyde metabolite by direct deamination of the parent compound and by deamination of its primary amine metabolite, desisopropyl propranolol.

Xenobiotics. such as the hallucinogenic agents mescaline "" and l-(2.5-dimethoxy-4-methylphenyl)-2-aminiv propane (DOM or STP ). " are oxidatively deami-nated. Primary amine metabolites arising from N-... 

The reduction of aromatic nitro and azo xenobiotics leads to aromatic primary amine metabolites. Aromatic nitro compounds are reduced initially to the nitroso and hydroxyl-amine intermediates, as shown in the following metabolic sequence ... 

In general, the reduction of both aromatic into and azo xenobiotics ultimately gives rise to the corresponding primary amine metabolites. These reactions may be summarized explicitely in the... 

The effect of smoking on the activity of CYP1A2 does not appear to have an affect on the plasma concentrations of the secondary TCAs. This is because CYP1A is not involved with the N-dealkylation to their primary amine metabolites. 

Desipramine is a dihydrodibenzazepine secondary amine TCA that also is the active metabolite of imipramine (Fig. 21.8). Desipramine appears to have a bioavailability comparable to the other secondary TCAs (Table 21.3). Desipramine is distributed into milk in concentrations similar to those present at steady state in maternal plasma. This drug is metabolized primarily by CYP2D6 to its 2-hydroxy metabolite and by CYP1A2 and CYP2C19 to its N-demethylated (primary amine) metabolite (Table 21.2). 

Hanson KL, VandenBrink BM, Babu KN, Allen KE, Nelson WL, Kunze KL (2010) Sequential metabolism of secondary alkyl amines to metabolic-inter-mediate complexes opposing roles for the secondary hydroxylamine and primary amine metabolites of desipramine, (s)-fluoxetine, and N-desmethyldi-Itiazem. Drug Metab Dispos 38 963-972... 

In summary, primary amine and monoalkyl derivatives of tryptamine have not yet been demonstrated to produce hallucinogenic effects in man or to consistently produce profound behavioral effects in animals. Admittedly, relatively few compounds have been examined, and few studies have been conducted. Nevertheless, present evidence suggests that these derivatives, by virtue of their inability to penetrate the blood-brain barrier and/or their rapid metabolism, may not be able to achieve adequate brain levels to elicit effects. In some cases, these factors may lead to masking of potential central effects by peripheral actions of the compounds or their metabolites. 

DeCaprio AP, Olajos EJ, Weber P, et al. 1982. Covalent binding of a neurotoxic -hexane metabolite conversion of primary amines to substituted pyrrole adducts by 2,5-hexanedione. Toxicol Appl Pharmacol 65 440-450. 

The first product in the oxidation of primary amines is a hydroxylamine as indicated in Figure 4.85. Hydroxylamines can be further oxidized to nitroso metabolites, which can be viewed as analogous to the oxidation of an alcohol to an aldehyde. If there is a hydrogen... 

FIGURE 4.85 Oxidation of primary amines leads to a hydroxylamine followed by a nitroso metabolite, which if there is a hydrogen on the a-carbon can rearrange to an oxime. Without such a hydrogen, as in the case of phentermine, no rearrangement is possible. 

The major metabolites of lidocaine formed from this part of the molecule are the amine (16), which is further oxidized to the para-phenol, N-dealkylation of the parent drug with loss of acetaldehyde to form the secondary amine, and a second N-dealkylation to form the primary amine (structure not shown). Although there are only a few major metabolites of lidocaine, with sensitive analytical methods it is likely that hundreds of minor metabolites could be detected. 

The biotransformation of clofexamide (4.33, Fig. 4.4), a compound with anti-inflammatory and antidepressant activities, was investigated in rats [18]. About 15% of the dose administered was found in urine as 2-(4-chlorophe-noxy)acetic acid (4.37). This metabolite was formed via the secondary amine 4.34, the primary amine 4.35, and the acid 4.36 resulting from oxidative deamination. However, direct formation of 2-(4-chlorophenoxy)acetic acid (4.37) from the parent compound (4.33) cannot be excluded. Clofexamide and its metabolite 4.34 also underwent hydroxylation on the aromatic ring, but these hydroxylated metabolites did not appear to be hydrolyzed. 

The cyclic metabolite 11.169 was also a substrate in further biotransformations, being (V-demethylated to the corresponding endocyclic imine, and oxidized to phenolic metabolites. Very little if any of the secondary amine metabolite (11.168) appeared to undergo direct (V-demethylation to the primary amine, in contrast to many other tertiary amines, presumably due to very rapid cyclization of the secondary amine facilitated by steric and electronic factors. The possibility for the iminium cation (11.169 H+) to become deprotonated (a reaction impossible for the iminium 11.166 in Fig. 11.20) should also drive the cyclization reaction. 

Deamination. Amine groups can be removed oxidatively via a deamination reaction, which may be catalyzed by cytochromes P-450. Other enzymes, such as monoamine oxidases, may also be involved in deamination reactions (see below). The product of deamination of a primary amine is the corresponding ketone. For example, amphetamine is metabolized in the rabbit to phenylacetone (Fig. 4.27). The mechanism probably involves oxidation of the carbon atom to yield a carbinolamine, which can rearrange to the ketone with loss of ammonia. Alternatively, the reaction may proceed via phenylacetoneoxime, which has been isolated as a metabolite and for which there are several possible routes of formation. The phenylacetoneoxime is hydrolyzed to phenylacetone. Also N-hydroxylation of amphetamine may take place and give rise to phenylacetone as a metabolite. This illustrates that there may be several routes to a particular metabolite. 

The enzyme found in the liver will deaminate secondary and tertiary aliphatic amines as well as primary amines, although the latter are the preferred substrates and are deaminated faster. Secondary and tertiary amines are preferentially dealky la ted to primary amines. For aromatic amines, such as benzylamine, electron-withdrawing substituents on the ring will increase the reaction rate. The product of the reaction is an aldehyde (Fig. 4.30). Amines such as amphetamine are not substrates, seemingly due to the presence of a methyl group on the a-carbon atom (Fig. 4.27). Monoamine oxidase is important in the metabolic activation and subsequent toxicity of allylamine (Fig. 4.31), which is highly toxic to the heart. The presence of the amine oxidase in heart tissue allows metabolism to the toxic metabolite, allyl aldehyde (Fig. 4.31). Another example is the metabolism of MPTP to a toxic metabolite by monoamine oxidase in the central nervous system, which is discussed in more detail in chapter 7. 

In general, EC reactions are typically observed according to the following general rank order (by relative ease of oxidation) o,p-quinol and o,p-aminophenol > tertiary amine > m-quinol rv phenol rv arylamine > secondary amine thiol > thioether primary amines, aliphatic alcohols. (HDVs) each redox active metabolite are obtained from the response across adjacent EC-Array sensors. These data are a reflection of the kinetic and thermodynamic components of electron transfer reactions. Since chemical structure is a critical determinant of an analyte s redox behavior, the intrinsic generation of an HDV with EC-Array provides qualitative information for each species. 

There has been revived interest in a-acetylmethadol as a result of its use in the maintenance of addicts (p. 304) and several pharmacokinetic(19) and pharmacological studies of the ester have been made. The acetate is characterized by a slow onset of action, a feature attributed to its conversion to an active metabolite,(40) and this proposal is supported by the isolation of two metabolic products from rats(41) and opioid addicts(42) that are effective analgesics. The compounds are the secondary and primary amines corresponding to a-acetylmethadol formed by successive N-demethylation and were detected by GCMS after conversion to trichloroacetamide derivatives. Authentic primary amine 15 was initially prepared by oxidizing a-(-)-acetylmethadol... 

The synthesis of IV-ribofuranosyltriazoles, for use as metabolite analogs of the purine-forming imidazoles, provides a different aspect of N-alkylation in the triazole series. Acid-catalyzed fusion of 4-nitrotriazole with tetra-O-acetyl-/3-D-ribofuranose gave 2-/5-D-ribofuranosyl-4-nitrotriazole (175°C, 45 min, 58%), accompanied by 24% yield of the 1-ribofuranosyl isomer. The acetyl groups were removed with cold methanolic sodium methoxide (85% yield), and the nitro group reduced to a primary amine with hydrazine hydrate over palladium in methanol (25°C, 93%) (72JHC1195). 

Many times, bisdcalkylation of a tertiary amine leads to the coiTe.sponding primary aliphatic amine metabolite, which is susceptible to further oxidation. For example, the bisdes-methyl metabolite of the H -histamine antagonist brompheniramine (Dimetane) undergoes oxidative deamination and further oxidation to the corresponding propionic acid metabolite."" Oxidative deamination is discussed in greater detail when we examine the metabolic reactions of secondary and primary amines. 

Secondary and Primary Amines. Secondary amines (cither patent compounds or metabolites) are susceptible to oxidative N-dealkylation. oxidative deamination, and N-oxi-dation reactions. - As in tertiary aminc.s. N-dealkylation of secondary amines proceeds by the carbinolamine path-... 

In primary aliphatic amines, such as phentermine. chlorphentcrmine (yx-chlotphentcrmine).- and amantadine. N-oxidation appears to be the major biotransformation pathway because a-carbon hydroxylation cannot occur. In hum-ans. chlorphentcrmine is N-hydroxylated extensively. About 30% of a dose of chlorphentermine is found in the urine (48 hours) as Al-hydroxychlorphentermine (free and conjugated) and an additional 18% as other products of N-oxidation (presumably the nitroso and nitro metabolites). In general, /V-hydroxylamines are chemically unstable and susceptible to spontaneous or enzymatic oxidation to the nitro.so and nitro derivatives. For example, the N-hydroxyl-amine metabolite of phentermine undergoes further oxiila-... 

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