The Metabolic Disposition of Etodolac in Rats, Dogs, and Man

Abstract

The metabolic disposition of etodolac (etodolic acid) was studied after oral and intravenous administration of the 14C-labeled or unlabeled drug to rats and dogs, and after oral administration of the drug to man. In all species, peak serum drug levels were attained within 2 hr after dosing. In rats and dogs, virtually all of the oral dose was absorbed; etodolac represented 95% of the serum radioactivity in rats and 75% in dogs. Serum levels in all species were generally dose-related. The elimination portion of the serum drug concentration/time curves was characterized by several peaks, which in rats were shown to be due to enterohepatic circulation. Tissue distribution studies in rats showed that radioactivity localized primarily in blood vessels, connective tissue, and highly vascularized organs (liver, heart, lung, and kidney) and that the rate of elimination of radioactivity from tissues was similar to that found in the serum. The apparent elimination half-life of etodolac averaged 17 hr in rats, 10 hr in dogs, and 7 hr in man. Etodolac was extensively bound to serum proteins. Liver microsomal cytochrome P-450 levels were unaltered in rats given etodolac daily for 1 week. The primary route of excretion in rats and dogs was via the bile into the feces. Preliminary biotransformation studies in dogs showed the presence of the glucuronide conjugate of etodolac in bile, but not in the urine. Glucuronide conjugates were not seen in the rat. Four hydroxylated metabolites in rat bile were tentatively identified. It was concluded that, in rats and dogs, etodolac is well absorbed, is subject to extensive enterohepatic circulation, undergoes partial biotransformation, and is excreted primarily into the feces.U

FUNCTIONAL INVOLVEMENT OF RAT ORGANIC ANION TRANSPORTER 2 (SLC22A7) IN THE HEPATIC UPTAKE OF THE NONSTEROIDAL ANTI-INFLAMMATORY DRUG KETOPROFEN

“…The NSAIDs are eliminated from the body mainly by the liver by biliary excretion and metabolism including glucuronidation in rats (Yesair et al, 1970;Sumner et al, 1975;Stierlin and Faigle, 1979;Cayen et al, 1981;Foster and Jamali, 1988;Dietzel et al, 1990;Iwakawa et al, 1991) except salicylate and sulindac. For salicylate, the renal and hepatic elimination occurs to a similar degree (Yue and Varma, 1982).…”

Etodolac: The chemistry, pharmacology, metabolic disposition, and clinical profile of a novel anti‐inflammatory pyranocarboxylic acid

“…40 Peak levels were attained 1 h after dosing, and t i during the terminal portion of the curve averaged 6.7 h. In another study4' in which subjects were given tablets con- Volume of distribution (L/kg) taining etodolac in single doses ranging from 25 to 1600 mg, dose-dependent increases in the AUC of serum etodolac were observed in the dose range of 400 to 1600 mg (inset to Fig. 8).…”

Species differences in the pharmacokinetics of recainam, a new anti‐arrhythmic drug

“…A drug free period of 1 week separated the doses. Blood was collected at 0.17, 0.33, 0.66, 1, 1.5, 2, 2.5, 3, 4, 5,6,8,12,16,20, and 24 h after each dose, and recainam concentrations were quantitated in plasma.…”

“…The study included a 1 week recovery period between dose administration. Heparinized blood was collected at 0.083, 0-17, 0.33, 0.66, 1, 1.5, 2, 3, 4, 5,6,7,8,10,12,15,18, and 24 h after dosing and plasma recainam concentrations were measured.…”