Primary and beta-secondary deuterium isotope effects in N-deethylation reactions.
Lidocaine (1), labeled specifically with deuterium in the alpha-methylene (lidocaine-d4,2) and beta-methyl (lidocaine-d6,3) carbon atoms of the terminal amino group, was used to probe the mechanism of oxidative N-deethylation by rat liver microsomes. The reaction rates were determined by measuring the formation of acetaldehyde colorimetrically. This general assay for oxidative N-deethylation reactions has the advantages of being rapid, producing a relatively stable colored derivative and being linear over the range of 0.25-4 mug of acetaldehyde formed per milliliter of incubate. Deuterium substitution at the methylene carbon atoms, the presumed site of initial oxygen insertion, revealed a kH/kD = 1.49 +/- 0.11 and a KmD/KmH = 1.23. Deuterium substitution on the terminal methyl groups showed a kH/kD = 1.52 +/- 0.10 and a KmD/KmH = 0.92. The results are explained in terms of both primary and secondary isotope effects on a possible rate-determining step in the N-deethylation sequence.
D000079:Acetaldehyde / Q000378:metabolism; D000818:Animals; D003640:Dealkylation; D003903:Deuterium; D066298:In Vitro Techniques; D007553:Isotope Labeling; D007700:Kinetics; D008012:Lidocaine / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats
D008012:Lidocaine; D003903:Deuterium; D000079:Acetaldehyde