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 toN-(N-ethylglycyl)-2,6-xylidine, andN-(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, andN-glycyl-2,6-xylidine with purified liver carboxylesterases. Rat liver microsomal carboxylesterase ES-10, but not carboxylesterase ES-4, hydrolyzed lidocaine andN-(N-ethylglycyl)-2,6-xylidine to 2,6-xylidine, identifying this esterase as a candidate enzyme in the metabolism of lidocaine.
Footnotes
- Abbreviations used are::
- LIDO
- lidocaine
- 3-OH-MEGX
- 3-hydroxy-N-(N-ethylglycyl)-2,6-xylidine
- MEGX
- N-(N-ethylglycyl)-2,6-xylidine
- GX
- N-glycyl-2,6-xylidine
- 3-OH-GX
- 3-OH-N-glycyl-2,6-xylidine
- 3-OH-LIDO
- 3-OH-lidocaine
- Me-OH-LIDO
- methylhydroxylidocaine
- 4-OH-XYL
- 4-hydroxy-2,6-xylidine
- XYL
- 2,6-xylidine
- BNPP
- bis-(nitrophenyl) phosphate
- P450
- cytochrome P450
- S-D
- Sprague-Dawley
- HPLC
- high-performance liquid chromatography
- LC/MS
- liquid chromatography/mass spectrometry
- Received December 5, 2001.
- Accepted February 22, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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