Etodolac is a chiral nonsteroidal anti-inflammatory
drug (
NSAID) that is marked 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 non-arthritic 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.