McMahon T F, Diliberto J J, Birnbaum L S
National Institute of Environmental Health Sciences, Division of Toxicology Research and Testing, Research Triangle Park, NC 27709.
Drug Metab Dispos. 1990 Jul-Aug;18(4):494-503.
Salicylic acid (SAL)-induced nephrotoxicity has been reported to be greater in older rats. To examine age- and dose-related changes in disposition and metabolism, male Fischer 344 rats aged 3, 12, and 25 months were administered single doses of 14C-SAL at 5,50, and 500 mg/kg po. At 5 mg 14C-SAL/kg, urinary excretion of 14C-SAL derived radioactivity (RA) followed first-order kinetics and was complete by 24 hr in 3- and 25-month-old rats, but not until 48 hr in 12-month-old rats. The percentage of administered 14C-SAL excreted as the oxidative metabolites 2,3- and 2,5-dihydroxybenzoic acid (2,3- and 2,5-diOH), unmetabolized SAL, or salicyl ester glucuronide (SA-AG) was unchanged with age. The percentage excreted as the ether glucuronide (SA-PC) was significantly decreased in 25-month-old rats, while the percentage excreted as the glycine conjugate, salicyluric acid (SUA) was significantly increased in 12- and 25-month-old rats. At 50 mg SAL/kg, urinary elimination shifted toward zero-order kinetics and was not complete until 48 hr in all age groups. The percentage of an administered dose of 14C-SAL found in urine as 2,3- and 2,5-diOH and SA-AG increased significantly in all age groups, while the percentage excreted as SUA decreased significantly. Twelve- and 25-month-old rats excreted a significantly greater percentage of the total dose as 2,3- and 2,5-diOH than 3-month-old rats at this dose. No SA-PG was detected at this dose in any age group. At 500 mg SAL/kg, mortality was observed in both 3- and 25-month-old rats and excretion of SAL-derived RA in urine was incomplete at 48 hr. However, data indicated a further shift in biotransformation toward increased production of oxidative metabolites and a decrease in SUA production. No significant overall differences were observed between 3- and 25-month-old rats in plasma levels of 14C-SAL following iv administration of 5 and 50 mg SAL/kg. However, elimination half-life (t1/2) was significantly increased in 25-month-old rats at 5 mg SAL/kg vs. 3-month-old rats. These results indicate that the age-related increase in acute nephrotoxicity of SAL may result from increased production of oxidative metabolites in older rats at higher doses of SAL.
