title: Involvement of liver carboxylesterases in the in vitro metabolism of lidocaine.
abstract: Although lidocaine has been used clinically for more than half a century, the metabolism has still not been fully elucidated. In the present study we have addressed the involvement of hydroxylations, deethylations, and ester hydrolysis in the metabolism of lidocaine to 2,6-xylidine. Using microsomes isolated from male rat liver, we found that lidocaine is mainly metabolized by deethylation to N-(N-ethylglycyl)-2,6-xylidine, and N-(N-ethylglycyl)-2,6-xylidine is mainly metabolized to N-glycyl-2,6-xylidine, also by deethylation. However, 2,6-xylidine can be formed both from lidocaine and N-(N-ethylglycyl)-2,6-xylidine, but not from N-glycyl-2,6-xylidine, in an NADPH-independent reaction, suggesting that the amido bond in these compounds can be directly hydrolyzed by esterases. To test this hypothesis, we incubated lidocaine, N-(N-ethylglycyl)-2,6-xylidine, and N-glycyl-2,6-xylidine with purified liver carboxylesterases. Rat liver microsomal carboxylesterase ES-10, but not carboxylesterase ES-4, hydrolyzed lidocaine and N-(N-ethylglycyl)-2,6-xylidine to 2,6-xylidine, identifying this esterase as a candidate enzyme in the metabolism of lidocaine.
authors.affiliation: Division of Clinical Chemistry, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden.
authors.forename: Stefan E H
authors.initials: SE
authors.lastname: Alexson
authors.forename: Margareta
authors.initials: M
authors.lastname: Diczfalusy
authors.forename: Magnus
authors.initials: M
authors.lastname: Halldin
authors.forename: Stellan
authors.initials: S
authors.lastname: Swedmark
mesh_terms: D000779:Anesthetics, Local / Q000378:metabolism*; D000818:Animals; D043182:Carboxylesterase; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism*; D006868:Hydrolysis; D006900:Hydroxylation; D066298:In Vitro Techniques; D008012:Lidocaine / Q000031:analogs & derivatives* / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D013045:Species Specificity; D013552:Swine
chemical_list: D000779:Anesthetics, Local; C091002:3-hydroxy-monoethylglycinexylidide; D008012:Lidocaine; C001306:glycinexylidide; C001173:monoethylglycinexylidide; D002265:Carboxylic Ester Hydrolases; D043182:Carboxylesterase