Etodolac Clinical Pharmacokinetics

Summary

Etodolac is a chiral nonsteroidal anti-inflammatory drug (NSAID) that is marketed as the racemate. Currently, the drug is available in several countries for the treatment of arthritis and the alleviation of pain.

Etodolac possesses several unique disposition features mainly due to its stereoselective pharmacokinetics. In plasma, the concentrations of the ‘inactive’ R-enantiomer are about 10-fold higher than those of the active S-enantiomer, an observation that is novel among the chiral NSAIDs. In common with other NSAIDs, the drug is highly plasma protein bound, and undergoes virtually complete biotransformation to oxidised metabolites and acyl-glucuronides. Etodolac is well absorbed, with maximal plasma concentrations attained within 1 to 2 hours in healthy volunteers. The area under the plasma concentration-time curve of racemic etodolac increases linearly with doses used clinically. The elimination half-life of etodolac is between 6 and 8 hours in plasma, and is similar for both enantiomers. The volume of distribution (Vd) of racemic etodolac is higher than that of most other NSAIDs mainly because of the extensive distribution of the S-enantiomer. The very large Vd of the S-enantiomer, compared with its antipode is, at least in part, due to its less extensive plasma protein binding. In addition to the unchanged drug, substantial concentrations of the acyl-glucuronides of etodolac are found in both plasma and the synovial fluid of patients with arthritis.

A limited amount of conjugated etodolac is found in the bile of patients following cholecystectomy. Hepatic cirrhosis has no effect on the pharmacokinetics of racemic etodolac, although the effect of hepatic dysfunction on the pharmacokinetics of the individual enantiomers has yet to be determined. In elderly nonarthritic individuals with excellent kidney function, aging does not affect the pharmacokinetics of etodolac. The pharmacokinetics of the drug in patients with renal failure have not been published, and may be important because the acyl-glucuronides are renally cleared.