Biotransformations hydroxylated metabolites

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. 

Metabolism/Excretion - Nevirapine is extensively biotransformed via cytochrome P450 (oxidative) metabolism to several hydroxylated metabolites. 

Another important situation occurs when the parent drug is biotransformed into a less efficacious and possibly more toxic metabolite. For example, if the concentration of the hydroxylated metabolite of imipramine (2-hydroxyimipramine) were increased, this TCA could lose its effectiveness while simultaneously increasing in toxicity (38). 

Biotransformation The process by which a drug is converted to more polar substances (i.e., metabolites), which are then eliminated from the body either in the urine or in the stool (e.g., demethylated and hydroxylated metabolites of tricyclic antidepressants the three metabolites of bupropion). 

Warner, N.A. Martin, J.W. Wong, C.S., Chiral polychlorinated biphenyls are biotransformed enantioselectively by mammalian c3tiochrome P-450 isozymes to form hydroxylated metabolites Environ. Sci Technol. 2009, 43, 114—121. 

A rather novel biotransformation that can occur as part of an aromatic hydroxylation process has been called the NIH shift whereby a substituent such as bromo, chloro, and fluoro at the position of hydroxylation undergoes migration to the adjacent position. Relevant examples are relatively few but this may be due to the lack of rigorous identification of ring-hydroxylated metabolites. 

Parenteral exposure is more hazardous than oral exposure gastrointestinal absorption is slow and incomplete. Fats and oils increase rotenone absorption from the gastrointestinal tract. Rotenone exhibits a significant first-pass effect following oral exposure. Biotransformation of rotenone in rats leads to hydroxylated metabolites (rotenolones). In addition, O-demethylation inactivates rotenone. Rotenone distributes to lipid-rich tissues, including the nervous system. Elimination of rotenone from the body is primarily through the fecal route. 

Fig. 31.1 Sequential steps of drug biotransformation. After uptake by the cell, a phenyl ring of a xenobiotic undergoes first a functionalization reaction (oxidation, phase I). The hydroxyl metabolite is then conjugated by addition of a sulfate group (phase II), before being exported from the cell by transporters (phase III) and excreted. P-450, cytochromes P-450 ST, sulfotransferases.

On incubation of propiomazine with a rat liver preparation, Robinson26 characterized the predominant biotransformation product as the aromatic ring hydroxylated metabolite. The metabolic product resulting from dealkylation of the 10-dialkylaminoalkyl substituent, which is a characteristic metabolite of most biologically active pheno-thiazine derivatives, was not detected in this study. 

The biotransformation of ephedrine proceeds via demethylation to norephedrine and via oxidative deamination followed by conjugation, in analogy to the metabolism of amphetamine. Over 90% is eliminated via the kidneys within 24 h, up to 75% unchanged, 8-20% as norephedrine and the rest after oxidative deamination. Methylephedrine is 33% unchanged and is 8% excreted as ephedrine. The excretion rate also depends on the pH of the urine. Desmethylpropylhexedrine and 4-hydroxypropylhexedrine, metabolites of propylhexedrine, can be determined in the urine [44]. Prolintane, a benzylbutylpyrrolidine product, is to some extent changed oxidatively in the liver. This mainly produces hydroxylated metabolites, but also produces... 

The 4-hydroxycomnarins undergo biotransformation similar to warfarin, forming hydroxylated metabolites at the 6 and 7 positions. These hydroxylated metabolites accoimt for 63 to 99% of the metabolic clearance of 4-hydroxycoumarins, including acenocoumarol. The metabolic clearances of R- and S-acenocoumarol are 6 and 66 times higher than those of R- and S-warfarin, respectively [68]. The metabolism of acenocoumarol is also stereoselective in favor of the S enantiomer. Sulphaphenazole competitively inhibits the 7-hydroxylation of R- and S-acenocoumarol and the 6-hydroxylation of S-acenocoumarol. Omeprazole acts as a partial inhibitor of 6- and 7-hydroxylation of acenocoumarol enantiomers [68]. 

The 4- and 5-hydroxylated metabolites of (R)- or (S)-propranolol were produced by biotransformation with two fungal strains, starting from either the racemic drug or pure enantiomers. The strain M50036 operated a... 

By carefully examining the fragmentation pattern of the metabolite and comparison with the mass spectra of the precursor molecule, it is often possible to determine not only the nature of the biotransformation, but also its position in the molecule. In the proceeding example, accurate mass measurement was used to determine that a hydroxyl group had been added to the benzene ring containing the fluorine substituent. 

In phase 1, the pollutant is converted into a more water-soluble metabolites, by oxidation, hydrolysis, hydration, or reduction. Usually, phase 1 metabolism introduces one or more hydroxyl groups. In phase 2, a water-soluble endogenous species (usually an anion) is attached to the metabolite— very commonly through a hydroxyl group introduced during phase 1. Although this scheme describes the course of most biotransformations of lipophilic xenobiotics, there can be departures from it. 

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