Glucuronidation reactions metabolic activation

In general, phase I reactions, such as oxidation and ra-demethylation are delayed in the neonate but are fully operational at or above adult levels by 4-6 months of age in the full-term neonate [27a-30]. Conjugation pathways, such as glucuronidation, do not approach adult values until 3 or 4 years of age. Sulfation activity does appear to reach adult levels in early infancy. For drugs that are subject to metabolism by both pathways, such as acetaminophen, the efficient activity of the sulfation pathway allows infants and children to compensate for low glucuronidation ability... 

Another therapeutic class to be briefly discussed is that of the lipid-lowering agents known as fibrates, e.g., clofibrate and fenofibrate (8.5). Here also, the acidic metabolite is the active form clofibrate (an ethyl ester) is rapidly hydrolyzed to clofibric acid by liver carboxylesterases and blood esterases [11], Human metabolic studies of fenofibrate (8.5), the isopropyl ester of fenofibric acid, showed incomplete absorption after oral administration, while hydrolysis of the absorbed fraction was quantitative [12], This was followed by other reactions of biotransformation, mainly glucuronidation of the carboxylic acid group. 

Hepatic metabolism accounts for the clearance of all benzodiazepines. The patterns and rates of metabolism depend on the individual drugs. Most benzodiazepines undergo microsomal oxidation (phase I reactions), including TV-dealkylation and aliphatic hydroxylation. The metabolites are subsequently conjugated (phase II reactions) to form glucuronides that are excreted in the urine. However, many phase I metabolites of benzodiazepines are pharmacologically active, with long half-lives. 

Disposition in the Body. Readily absorbed after oral or rectal administration and slowly absorbed after intramuscular injection. The major metabolic reactions are C-glucuronidation at the 4-position of the pyrazolidine ring and 4-hydroxylation of one of the phenyl rings to form the active metabolite, oxyphenbutazone 3-hydroxylation of the butyl side-chain to form 3 -hydroxyphenylbutazone, and formation of 4,3 -dihydroxyphenylbutazone also occur. About 61% of a dose is slowly excreted in the urine over a period of about 21 days, together with up to 27% in the faeces. Of the material excreted in the urine, the 4-C-glucuronide of phenylbutazone accounts for about 40%, free phenylbutazone and free oxyphenbutazone about 1%, 4,3 -dihydroxyphenylbutazone about 6%, 3 -hydroxy-phenylbutazone about 3%, and the remainder consists of the C-glucuronide of 3 -hydroxyphenylbutazone (about 12%), oxyphenbutazone 0-glucuronide and two other metabolites. 

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