Acetanilide, metabolism

Pretreatment with the Type I substrate, ethylmorphine, resulted in 100% mortality in both rats and mice, and aminopyrine pretreatment resulted in 100% and 64% mortality in rats and mice, respectively, exposed to disulfoton (Pawar and Fawade 1978). Nickel chloride, cobalt chloride, or cycloheximide decreased the levels of cytochrome bs, cytochrome c reductase, and total heme in rats (Fawade and Pawar 1983). These electron transport components were further decreased in rats pretreated with these inhibitors and given a single dose of disulfoton. Data from this study suggests an additive effect, since disulfoton also decreases the activities of these components. Evidence of an additive effect between disulfoton and these metabolic inhibitors was suggested by the decrease in ethylmorphine N-demethylase and acetanilide hydroxylase activities when rats were given an inhibitor followed by disulfoton. In another experiment, these inhibitors decreased the activity of delta-aminolevulinic acid synthetase, but this decrease was reversed when disulfoton was administered. 

The oral administration of antibiotics resulted in the production of germfree characteristics with respect to propachlor metabolism in rats ( ) and pigs (31), i.e. no 2-methylsulfonyl acetanilides were formed and only MAP metabolites were excreted. This observation may have economic implications. It is possible that the growth stimulation observed upon incorporation of antibiotics into animal feed could be effected by the suppression of such mechanisms. This could be accomplished either by the prevention of the metabolic formation of new xenobiotics of unknown biological activities or by the conservation of detoxication energy or both. 

Species differences in the metabolism of propachlor are summarized in Table II. All species studied metabolized propachlor in the MAP. Obvious, but unexplained differences are that the rat excreted no cysteine conjugate and the chicken formed no methylsulfonyl-containing metabolites. The absence of methylsulfonyl formation by chickens is thought due to the low biliary secretion of first pass metabolites. The ruminant (sheep) excreted large amounts of cysteine conjugate in urine which is also not explained. We do not know if the intestinal flora are involved in the formation of the methylsulfonyl acetanilides isolated from sheep urine. 

Figure 7.5 Metabolism of (a) acetanilide into the toxic species (b) aniline and the safer analgesic (c) acetaminophen (paracetamol).

The rates of metabolism are also impaired in vitamin deficiency states (especially vitamin A, vitamin B, C and E). Starvation in mice leads to decrease in the rates of metabolism of certain drugs like pethidine, acetanilide, hexobarbitone etc. Ethanol increases the hepatic content of monooxygenase enzymes and cytochrome P450 on chronic ingestion. 

Ademola, J.I., Wester, R.C., Maibach, H.I. (1993). Absorption and metabolism of2-chloro-2,6-diethyl-N-(butoxymethyl)acetanilide (butacblor) inhuman skin in vitro. Toxicol. Appl. Pharmacol. 121 78-86. 

Furthermore, it has to be noted that the nitro groups in the NMCs are metabolized by microorganisms and animals such as fish and rats. It is known that aromatic amines (substituted anilines) are acetylated to acetanilides. Some of these compounds possess anti-androgenic properties [351 b, c, d]. It is supposed that some N-acetylated metabolites of NMCs, e.g. 2-methyl-3-nitro-4-methoxy-5-ferf-butyl-acetanilide (metabolite of musk ambrette) and 4-ferf-butyl-2,6-di-methyl-3,5-dinitro-acetanilide (metabolite of musk xylene) are bound to the androgen receptor (AR) and may act as weak anti-andxogens [351 e]. 

FIGURE 16.1 Metabolism of acetanilide. The major route of metabolism is via hydroxylation to form 4-hydroxyacetanilide (acetaminophen). Less than 1% is deacety-lated to form anilme. 

Relative to the fate in humans of the l pes of compounds just discu.s.sed. Brudie and Axelrod " " point out that acet-anilid and phenacetin are metabolized by two different routes. Acctaniiid is metabolized primarily to Af-acetyl-p-aminophenol and acetaminophen and only a small amount to aniline, which they showed to be the precursor of phenyl-hydroxylamine. the compound re.sponsible for methcmoglobin formation. Phenacetin is mostly dccthylated to acetaminophen. whereas a small amount is convened by dcacctylation top-phenetidinc. also responsible for methemoglobin formation. With both acetanilid and phenacetin. the metabolite acetaminophen is believed to be responsible for the analgesic activity. Because of the toxicity described above, both are no longer available, replaced primarily by acetaminophen. 

Investigations into drugs suspected of causing cancer in humans have included aryl amine derivatives such as Paracetamol (17a)61 and phenacetin (17b). Metabolism of acetanilide (17c) yields aniline, and of 17b A-hydroxyphenacetin (18)62, in accord with views on mechanisms of toxicity as discussed in the next section. Tumor formation was induced in rats at excessively high dose levels and only under certain conditions. Drugs found to cause methemoglobinemia include antipyrine, acetanilide, sulfanilamide, sul-fapyridine, sulfathiazole, sulfonal and thional. 

JD Baty, RM Lindsay, WR Fox, RG Willis. Stable isotopes as probes for the metabolism of acetanilide in man and the rat. Biomed Environ Mass Spectrom 16 183-189, 1988. 

Properties of MAP and preMAP conjugates which influence the extent of the enterohepatlc circulation of intact MAP and preMAP metabolites are not known. Differences in enterohepatlc circulation can be deduced from levels of excretion of MAP and preMAP metabolites by control rats and rats with cannulated bile ducts. Data from 2-chloro- isopropylacetanilide (10) and naphthalene (11) metabolism studies are given in Table II. It is apparent that the acetanilide biliary MAP metabolites were not absorbed from the intestine for excretion as mercapturic acid, but were absorbed as intestinal catabolites of MAP metabolites (23%) and excreted with the urine. 

Sulfoxide Reduction. Reduction of the sulfoxide of the mercapturic acid of 2-chloro-f+-isopropylacetanilide by Intestinal microflora has been shown in vitFo (9), but has not been demonstrated to occur in tissues. The excretion of this mercapturate sulfoxide, which is excreted into the intestine with the bile, in feces from germfree rats dosed with the acetanilide is vivo evidence for the reductive function of the intestinal microflora (49) in MftP catabolism. This reduction, in addition to deacetylation, is another source for cysteine conjugates which can be translocated to the tissues for metabolism or excretion, or remain in the intestine and further catabolized by the microflora. 

In chickens, the mechanism did not involve amide hydrolysis (which occurred in the metabolism of this acetanilide) with subsequent N-... 

A similar 2-methylsulfonyl acetanilide was formed in the metabolism of -dimethylamlnobenzonitrile (32). in this case very complex metabolism went on prior to GSH conjugation (Figure 4). 

Figure 4. Proposed pathway for metabolism of -dimethylaminobenzo-nitrile to a methyIsulfonyl containing acetanilide. Bracketed L J intermediates and processes are proposed. R= -NC(C 4)...

Bio-oxidation and acetanilide and metabolic conversion of phenylbutazone gave rise to two better tolerated drug molecule used frequently and profusely in the therapeutic armamentarimn. Explain. 

The structure-activity relationships of p-aminophenol derivatives have been widely studied. Based on the comparative toxicity of acetanilide and acetaminophen, aminophenols are less toxic than the corresponding aniline derivatives, although p-aminophenol itself is too toxic for therapeutic purposes. Etherification of the phenolic function with methyl or propyl groups produces derivatives with greater side effects than with ethyl groups. Substituents on the nitrogen atom that reduce basicity reduce activity unless that substituent is metabolically labile (e.g., acetyl). Amides derived from aromatic acids (e.g., N-phenylbenzamide) are less active or inactive. 

The only report on the reactions of GAC-sorbed nitrogen compounds (Hwang et al., 1990) similarly indicated that sorbed anilines were converted by HOCl to oxidative coupling products such as azobenzenes (89), unlike solution reactions with HOCl that led to ring substitution. Additional compounds such as formanilides and acetanilides were also identified in some cases the mechanisms of formation of these N-substituted derivatives are unknown, although similar N-acyl derivatives have been reported to occur during the metabolism of anilines (Freitag et al., 1984). 

Studies on the acetate of A -hydroxy-AAF indicated that esterification of the hydroxamic acid could be the requisite transformation of an aromatic amine to an ultimate carcinogen. Bioassays indicated that A -acetoxy-AAF resembled direct-acting carcinogens in producing subcutaneous tumors at the site of injection. Unlike /V-hydroxy-AAF, this acetate ester reacted in vitro with various cellular macromolecules (339, 410). The metabolic activation of AAF and decomposition of A -acetoxy-AAF to an electrophile are illustrated in Fig. 1. The possibility that -hydroxy-AAF was esterified in vivo to sulfate or phosphate esters has been examined. Evidence that sulfate esters may be involved in the formation of the ultimate carcinogen of AAF has been supported by several in vivo bioassays. Coadministration of acetanilide, which depletes the intracellular level of sulfate, reduced the carcinogenicity of AAF (487). Coadministration of sulfate ion with AAF enhanced its activity as a liver carcinogen (97). 

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