Lidocaine (6, Figure 3) is a local anesthetic and antiarrhythmic drug in wide use since over five decades. The compound is very resistant to chemical hydrolysis even in strongly acidic or basic media. Yet, despite this high chemical stability, metabolic hydrolysis to 2,6-xylidine (7, Figure 3) represents a major pathway in mammals, with considerable interspecies differences in its extent. This may be due in part to the fact that N-dealkylated and pra-hydroxylated metabolites of lidocaine also undergo enzymatic hydrolysis, and do so with differing substrate selectivities. In humans, hydrolysis of the amide bond represents the major metabolic pathway, accounting for about 75% of the amount excreted in urine.5 Investigations using human liver slices have shown that 2,6-xylidine is produced by direct hydrolysis of lidocaine.15 Furthermore, a liver microsomal carboxylesterase very effectively hydrolyzed lidocaine and its mono-N-deethylated metabolite, but not its di-N-deethylated metabolite.16 These findings prove the different substrate selectivities of the oxidized metabolites of lidocaine toward hydrolases. More importantly, the demonstration that carboxylesterases are able to

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