Ring hydroxylation, metabolism

In order to clarify the problem of the position at which metabolic ring hydroxylation of phenothiazine drugs occurs, the nuclear magnetic resonance (NMR) spectra of some substituted phenothiazines were investigated. Although the application of NMR spectroscopy... 

Aromatic amines are initially metabolized by aromatic and A -hydroxylation (oxidation reactions) and Y-acetylation. Following aromatic ring hydroxylation, the ring structure may be further conjugated with glucuronic acid or sulfate (Parkinson 1996). N-hydroxylation results in the potential methemoglobin-generating metabolite,... 

Photolytic. When propachlor in an aqueous ethanolic solution was irradiated with UV light (>, = 290 nm) for 5 h, 80% decomposed to the following cyclic photoproducts W-isopropyloxindole, W-isopropyl-3 hydroxyoxindole, and a spiro compound. Irradiation of propachlor in an aqueous solution containing riboflavin as a sensitizer resulted in completed degradation of the parent compound. 3-Hydroxypropachlor was the only compound identified in trace amounts which formed via ring hydroxylation (Rejtb et al, 1984). Hydrolyzes under alkaline conditions forming W-isopropylaniline (Sittig, 1985) which is also a product of microbial metabolism (Novick et al., 1986). 

Preston BD, Miller JA, Miller EC. 1983. Non-arene oxide aromatic ring hydroxylation of 2,2,5,5 -tetrachlorobiphenyl as the major metabolic pathway catalyzed by phenobarbital-induced rat liver microsomes. J Biol Chem 258 8304-8311. 

Recently the hydroxy metabolites of various sulfonamides could be Isolated and purified, so that specific HPLC techniques could be developed (22,23). As shown in Figure 1, sulfadimidine can be metabolized by hydroxylation at the 5 and 6 position of the pyrimidine ring and by the acetylation- deacetylation pathway (21). After hydroxylation, the metabolites may become glucuronidated and also acetylated (Figure 2). The hydroxy metabolites are microbiologically active and they can be potentiated by trimethoprim (13). 

The major pathways for its metabolism include ring hydroxylation, with subsequent glucuronide conjugation and A-acetylation. Hydralazine exhibits a first-pass effect in that a large part of an orally administered dose is metabolized before the drug reaches the systemic circulation. The first-pass metabohsm occurs in the intestinal mucosa (mostly A-acetylation) and the hver. The primary excretory route is through renal elimination, and about 80% of an oral dose appears in the urine within 48 hours. About 10% is excreted unchanged in the feces. 

The slight conformational modification of the A ring (revealed by X-ray diffraction), which probably comes from an interaction between the fluorine on C-9 and the axial OH on C-1, could contribute to the differences of affinity. However, X-ray structure of the cocrystallized form of fluorocortisol with the glucocorticoid receptor does not explain the impact of fluorine on the increase in affinity (cortisol = 0.67 pM versus 9a-fluorocortisol Xj = 0.027 The fluorine at C-9 can reduce the oxidative metabolism of hydroxyl-11. Oxidation of OH-11 into ketone is fast for the cortisol and is accompanied by the loss of biological activity. However, this hypothesis would imply metabolites to contribute to the mineralocorticoid activity. 

The different MAOIs are metabolized via different pathways but tend to have extensive first-pass effects that may substantially decrease bioavailability. Tranylcypromine is ring hydroxylated and /V-acetylated, whereas acetylation appears to be a minor pathway for phenelzine. Selegiline is /V-demethylated and then hydroxylated. The MAOIs are well absorbed from the gastrointestinal tract. 

N-hydroxylation is not the only or major route of metabolism in vivo, nor is it the only reaction catalyzed by the microsomal enzymes. Ring hydroxylation is the major route of metabolism, the products of which are not carcinogenic. These alternative routes of metabolism are inducible in vivo by pretreatment with agents such as phenobarbital and 3-methylcholanthrene (see chap. 5). 

Clearly, the presence of the four chloro substituents in TCDD enhances its metabolic stability via a depression of the rate of ring hydroxylation. Of course, the parallel changes induced in its lipophilicity and molecular size may also contribute to the observed enhance-... 

A number of drugs having aromatic rings are metabolized by hydroxylation in the liver,225-227 e.g., in the metabolism of mepivacaine (368), isomeric 3-hydroxy (370) and 4-hydroxy compounds have been isolated, out of which 370 has been shown to be formed through the involvement of arene oxide 369.228... 

By far the most predominant metabolic pathway for water-soluble azo dyes is cleavage of the azo linkage by azoreductase of the liver and extrahepatic tissue or by intestinal microflora in the body [25,26], Oxidative metabolism occurs for lipid-soluble dyes, e.g., solvent dyes. Three oxidation pathways are known for such dyes (1) C-(ring-)hydroxylation, (2) A-hydroxylation at a primary or secondary amino group or (3) by stepwise oxidation of the methyl groups of dimethylamino compounds (demethylation). All three oxidative degradation ways leave the azo bond intact. For further details of the mechanisms, see [27,28],... 

---