Figure 3 The structure of lidocaine (6), 2,6-xylidine (7), and levetiracetam (8). The figure also shows thalidomide (9) and some of its products of spontaneous hydrolysis observed in vivo and in vitro.
efficiently hydrolyze some amides points to the near impossibility of correctly assessing their full range of potential substrates.
Another interesting amide is levetiracetam (8, Figure 3), a recent antiepileptic agent whose metabolism in humans is almost exclusively CYP-independent (oxidative metabolites represent p2.5% of a dose).17 Indeed, this hydrophilic compound was excreted renally unchanged for two-thirds of the dose, whereas a quarter of the dose was accounted for by its acidic metabolite resulting from hydrolysis of the primary carboxamide group. In vitro investigations have confirmed that the reaction was catalyzed by a serine hydrolase, most probably a carboxylesterase found in human liver, red cells, and most likely other tissues.
Thalidomide (9, Figure 3) is well known for its high teratogenicity and for causing the greatest drug-related tragedy in history. Recently, new clinical uses have been discovered that render thalidomide useful in alleviating symptoms in lepra and even HIV infections. Although the underlying mechanisms are only poorly understood, some of the activities of thalidomide may be related to its capacity to inhibit the production of tumor necrosis factor alpha (TNF-a).5,18
Parallel to rapid inversion of configuration and very low rates of hydroxylations, thalidomide is rapidly hydrolyzed to ring-opened products.18-21 All four amide bonds of the molecule are susceptible to hydrolytic cleavage at pH>6, and the reactions are nonenzymatic and base-catalyzed. The main urinary metabolites in humans were shown to be 2-phthalimidoglutaramic acid (10, about 50% of a dose) and a-(o-carboxybenzamido)-glutarimide (11, about 30% of a dose). Metabolites 12 and 13 were minor. Metabolite 11 was the main product in rats and dogs. Toxicological investigations revealed that of the 12 hydrolysis products of thalidomide only the three containing the intact phthalimido moiety retained teratogenic activity, namely metabolites 10, 12, and 13.
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