Pharmacological properties of five diclofenac metabolites identified in human plasma

Abstract

Five metabolites of diclofenac sodium (Voltarol) have been identified in human plasma. All five metabolites were more than 50 times less potent than diclofenac in inhibiting PGE2 production in zymosan-stimulated mouse macrophages and LTC4 synthesis was not inhibited in these cells. Anti-inflammatory activity (adjuvant arthritis and carragheenan-induced paw oedema in rats) and analgesic activity (phenyl-p-benzoquinone writhing, mouse) of the metabolites were at least 10 times lower when compared to diclofenac. There was a good correlation between in vitro PGE2 inhibition and in vivo activities for diclofenac and its metabolites indicating that inhibition of prostaglandin synthesis is a major mechanism responsible for their pharmacological actions.

Constitutive cyclooxygenase (COX-1) and inducible cyclooxygenase (COX-2): Rationale for selective inhibition and progress to date

“…A related series of aryl sulfonamides was investigated at Schering AG leading to the identification of the phenoxyindanone CGP 28238. 79 Continued interest in this class, most notably in Japan, has led to the discovery of T-61480 and FR115068.81 The low ulcerogenicity reported for these latter two compounds suggests that they will also demonstrate COX-2 selectivity. No additional COX SAR studies exist regarding selectivity for compounds of this class.…”

Diclofenac and metabolite pharmacokinetics in children

“…Diclofenac metabolites in man have been described in urine and plasma after single dose administration (16,18,35). These comprise 4′‐hydroxy, 5′‐hydroxy, 3′‐hydroxy, 4′,5′‐hydroxy and 3′‐hydroxy‐4′‐hydroxy‐methoxy diclofenac in adult volunteers.…”

Mimicking P450 processes and the use of metalloporphyrins

“…Diclofenac (13), one of the most frequently used anti-inflammatory drugs, is metabolized in humans by cytochrome P 450 enzymes to hydroxyl derivatives, among which 4'-hydroxydiclofenac (13.1), the major metabolite, and 5-hydroxydiclofenac (13.2) were isolated and characterized [96][97][98]. Some metabolites resulting from oxidative decarboxylation of diclofenac mediated by cytochrome P 450 enzymes have also been reported [99].…”