Tolmetin is a non-steroidal anti-inflammatory drug that non-selectively inhibits human COX-1 and -2 [1].
The cyclooxygenase (COX) is a therapeutic target for preventing cancer. Two isoforms of COX have been identified: COX 1 and COX 2. COX 1 has been constitutively expressed in most tissues and involved in mediating production of prostaglandins that control normal physiological functions, such as maintenance of the gastric mucosa and regulation of renal blood flow. COX 2 is undetectable in most normal tissues [2].
In vitro: Tolmetin inhibited the activity of human COX-1 and -2 with IC50 values of 0.35 and 0.82 μM, respectively [1]. Tolmetin was a competitive and reversible inhibitor of prostaglandin synthetase [3].
In vivo: In rats, pretreatment with tolmetin reduced prostaglandin synthesis by minces of renal medulla. Incubation of medullary tissue with tolmetin decreased prostagland production. In anesthetized dogs, Tolmetin reduced renal blood flow and shifted the distribution of renal cortical flow from the inner cortex toward the outer cortex [4].
References:
[1] Warner T D, Giuliano F, Vojnovic I, et al. Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis[J]. Proceedings of the National Academy of Sciences, 1999, 96(13): 7563-7568.
[2] Dannenberg A J, Altorki N K, Boyle J O, et al. Cyclo-oxygenase 2: a pharmacological target for the prevention of cancer[J]. The lancet oncology, 2001, 2(9): 544-551.
[3] Taylor R J, Salata J J. Inhibition of prostaglandin synthetase by tolmetin (Tolectin, McN-2559), a new non-steroidal anti-inflammatory agent[J]. Biochemical pharmacology, 1976, 25(22): 2479-2484.
[4] Noordewier B, Stygles V G, Hook J B, et al. Effect of tolmetin on renal function and prostaglandin metabolism[J]. Journal of Pharmacology and Experimental Therapeutics, 1978, 204(2): 461-468.
