Heterogeneity of changes on the disposition of aspirin in rats with CCl4-induced chronic liver damage.

The profile of urinary salicylate metabolites was determined after the oral administration of acetylsalicylic acid (ASA) to CCl4-cirrhotic rats, CCl4-cirrhotic rats treated with colchicine for 1 month, and control groups. The following enzymatic activities were determined: liver and plasma ASA-esterase, liver UDP-glucuronyltransferase, and liver aniline hydroxylase. The time-course of plasma concentration of salicylates in similar groups was followed after the intraperitoneal administration of salicylic acid (SA) or gentisic acid (GA). The cirrhotic animals showed a lack of urinary glucuronates and an increase in urinary gentisic and salicylic acids. The activities of plasma and liver ASA-esterases were increased significantly in cirrhosis, whereas aniline hydroxylase was reduced and UDP-glucuronyltransferase remained unchanged. The plasma half-lives of salicylates were reduced in the cirrhotic animals regardless of the administered parent compound. Colchicine treatment reversed almost completely the alterations. The heterogeneity of liver metabolic dysfunctions present in chronic liver disease was demonstrated. It is emphasized that the pharmacokinetic alterations produced by liver damage are the result of a complex set of factors involving changes in the hepatic circulation, protein binding, and the existence of other routes of elimination.