Metabolism of p-(cyclopropylcarbonyl)phenylacetic acid (SQ 20,650). Species Differences.

Abstract

The metabolism of p-(cyclopropylcarbonyl)phenyl[14C]acetic acid (I-14C), a nonsteroidal anti-inflammatory agent, has been studied in rats, dogs, and monkeys. Animals were given single intravenous or oral doses of 5 and 50 mg of I-14C/kg. In all cases, 72-88% of the administered dose was excreted in urine, with most of the radioactivity appearing within 24 hr after dosing; less than 11% was found in feces. The half-life (t1/2) of radioactivity in monkey or dog plasma was 1 and 5 hr. respectively, after the oral or intravenous administration of a 5-mg dose of I-14C per kg. At 50 mg/kg, these half-lives increased to 3.5 and 7.7 hr. respectively. More than 90% of the radioactivity in plasma of both species was associated with unchanged drug. Species differences exist in the biotransformation of I. Rat urine contained 93-97% I; 2-6% (alpha-cyclopropyl-alpha-hydroxy-p-tolyl)acetic acid (II); and approximately 1% as conjugates. Monkey urine contained I-glucuronide (88%) and unconjugated II (7-10%). In the dog, I-taurine accounted for 27% of the radioactivity found in urine; II and its taurine conjugate accounted for 20 and 30%, respectively; a small quantity of II-glycine (3%) was also detected. There are three minor metabolites that have not been identified. Metabolite II isolated from dog urine was shown to be dextrorotatory.