RT Journal Article SR Electronic T1 Deacetylation of diltiazem by rat liver. JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 122 OP 126 VO 15 IS 1 A1 E LeBoeuf A1 O Grech-BĂ©langer YR 1987 UL http://dmd.aspetjournals.org/content/15/1/122.abstract AB The enzyme system mediating the hydrolysis of the calcium antagonist diltiazem to give deacetyldiltiazem was characterized in the rat. Tissue distribution studies showed that the highest level of activity was mainly localized in the microsomal fraction of the liver. Some activity was also detected in the red blood cells. The kinetics of the enzymatic reaction demonstrated that the formation of deacetyldiltiazem increased linearly with time up to 60 min and with protein content up to 7.8 mg. Apparent Km and Vmax values calculated from a Lineweaver-Burk plot were 0.17 X 10(-3) M and 0.013 mumol/mg of protein/min. Mercuric chloride, silver nitrate, and cupric chloride at concentrations of 0.6 X 10(-3) M decreased the diltiazem deacetylase activity to 47%, 24%, and 19%, respectively, as compared to control incubations. At a concentration of 6.7 X 10(-8) M, cadmium sulfate decreased the hydrolysis of diltiazem by 40%, whereas cobaltous sulfate at concentrations of 10(-3) M did not affect the deacetylation activity. The hydrolysis reaction was depressed by the organophosphorus compounds, bis-p-nitrophenylphosphate and diisopropyl fluorophosphate to 31% and 0%, respectively, at concentrations of 10(-6) M. Eserine sulfate at a concentration of 2.2 X 10(-4) M, and disulfiram and aspirin at concentrations of 10(-3) M decreased the diltiazem deacetylase activity to 17%, 71%, and 79%, respectively. Rifampicin and phenacetin at concentrations of 10(-3) M did not inhibit the hydrolysis reaction. In vivo pretreatment of the rats with phenobarbital increased the in vitro diltiazem deacetylase activity 3.2-fold, whereas 3-methylcholanthrene did not affect the enzymatic hydrolysis of diltiazem.