PRIMARY AND BETA-SECONDARY DEUTERIUM-ISOTOPE EFFECTS IN O-DEETHYLATION OF PHENACETIN

Phenacetin (p-ethoxy acetanilide) specifically labeled with deuterium in the .alpha.-methylene or .beta.-methyl groups of the p-ethoxy function was used to study the oxidative deethylation of phenacetin by rabbit liver microsomes. The slower deethylation of p-[1,1-2H]ethoxy acetanilide compared with phenacetin [kH/k2H = 1.61 .+-. 0.19] supports hemiacetal formation as the rate determining step in the in vitro conversion of phenacetin to p-hydroxy acetanilide. Essentially no .beta.-secondary deuterium isotope effect (kH/k2H = 1.03 .+-. 0.09) was found as the result of deuterium substitution in the methyl group of the p-ethoxy function. The Km values of phenacetin (56 .+-. 2 .mu.M), p-[1,1-2H]ethoxy acetanilide (56 .+-. 5 .mu.M), and p-[2,2,2-2H]ethoxy acetanilide (50 .+-. 2 .mu.M) were all similar.