Tolbutamide, methyl oxidation

Hydroxylation of the benzylic methyl group of tolbutamide, the preferred site of oxidative attack by CYP2C9 (22), generates hydroxytolbutamide. Hydroxytolbutamide is rapidly oxidized by other enzymes, presumably aldehyde oxidase and/or alcohol dehydrogenase (ALD), to form the major isolated metabolite, the benzoic acid analog. 

Replacement of a vulnerable moiety such as a methyl group by a less readily oxidized chlorine was used to transform the short-acting tolbutamide (3.23), an oral antidiabetic, into the long-acting chlorpropamide (3.24), with a half-life sixfold greater than its parent. 

Glidazide. Chemically, gliclazidc. l-(3-azabicycln f3.3.0]oct-3-yl)-3-/>-lolylsulphonylurea (Diamicron), it very similar to tolbutamide, with the exception of the hi-cyclic heterocyclic ring found in glidazide. The pyrrolidiiK increases its lipophilieity over that of tolbutamide, which increases its half-life. Even so. the /s-methyl is. susceptible to the same oxidative metabolic fate as ob.served for tolbutamide. namely, it will be metabolized to a carboxylic acid. 

The older first-generation sulfonylureas are extensively metabolized and primarily excreted renally. Tolbutamide is transformed by oxidation of the benzylic methyl group, yield-inga hydroxymethyl metabolite, (la), which is further oxidized to the corresponding carboxylic acid, (lb). These metabolites have little activity. 

The oxidation of the methyl group begins generally with the formation of the hydroxymethyl analog and continues usually until the carboxyl step. This is observed for simple componnds like camphor or 2-methyl-pyridine but also for drugs like tolbutamide and alpidem, explaining the relatively short half-life of these latter compounds. 

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