Etodolac Clinical Pharmacokinetics

Abstract

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.

Single-dose safety and pharmacokinetic evaluation of fluorocoxib A: pilot study of novel cyclooxygenase-2-targeted optical imaging agent in a canine model

“…[37][38][39][40] Metabolism and elimination of NSAIDs is via the liver followed by renal excretion. The dog converts indomethacin to indomethacin glucuronide, which is excreted in the bile.…”

The R -enantiomer of the nonsteroidal antiinflammatory drug etodolac binds retinoid X receptor and induces tumor-selective apoptosis

“…Unlike all other chiral NSAIDs, the two enantiomers of etodolac are not metabolically interconvertible. Moreover, the R-enantiomer is metabolized much more slowly than the S-enantiomer, and it accumulates to 10-fold higher concentrations than the S-enantiomer in plasma (11). In a recent study, sufficient plasma levels of R-etodolac were achieved after oral gavage in a xenograft prostate cancer model to diminish the growth of the transplanted tumor (12).…”

Enhanced clearance of leukemic lymphocytes in B-cell chronic lymphocytic leukemia with etodolac

“…3 Etodolac selectively inhibits cyclooxygenase-2, 4 and it is approved for use in various parts of the world for treatment of degenerative joint disease and rheumatoid arthritis and for use as an analgesic. 5 We report the chance observation that racemic etodolac lowers the lymphocyte count in a patient with B-CLL and show that challenges with 13 other nonsteroidal anti-inflammatory drugs (NSAIDs) produced no significant effect. We also present studies to show that at standard anti-inflammatory doses, racemic etodolac achieves this action by enhancing the selective clearance rather than by the direct killing of leukemic lymphocytes.…”