RT Journal Article SR Electronic T1 Paraoxon hydrolysis vs. covalent binding in the elimination of paraoxon in the rabbit. JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 640 OP 645 VO 13 IS 6 A1 E G Butler A1 H W Eckerson A1 B N La Du YR 1985 UL http://dmd.aspetjournals.org/content/13/6/640.abstract AB Hydrolysis and covalent binding to nonessential esterases are two biochemical processes which can prevent paraoxon from reacting with the essential enzyme, acetylcholinesterase. Both processes have been proposed as the primary route of paraoxon detoxification in vivo. These experiments were designed to assess the relative contribution of each pathway to the disappearance of paraoxon in the rabbit. In vitro, paraoxon disappeared from whole rabbit blood with a t 1/2 of 17.7 sec. Hydrolysis by paraoxonase (EC 3.1.1.2) accounted entirely for this disappearance and covalent binding contributed essentially nothing. In vivo, following an iv injection of 0.15 mg/kg paraoxon, serum paraoxonase hydrolyzed as much as 41% of the injected dose within the first 30 sec. Pretreatment of rabbits with an ip injection of tri-o-tolyl phosphate eliminated more than 95% of the paraoxon binding sites. However, pretreatment with tri-o-tolyl phosphate had no significant effect on the t 1/2 or volume of distribution of paraoxon, indicating that covalent binding sites did not contribute significantly to the clearance of paraoxon from whole rabbits under these conditions. Hydrolysis of paraoxon by tissue paraoxonases, in addition to that catalyzed by paraoxonase in the blood, could account for its rapid metabolism. These findings demonstrate that paraoxonase has a major role in the disappearance of paraoxon in the rabbit. This suggests that susceptibility of people to chronic paraoxon poisoning may vary, according to their inherited level and type of serum paraoxonase.