A New Metabolite of Diclofenac Sodium in Human Plasma

Abstract

1. Among the phenolic metabolites of diclofenac in human plasma, an unknown compound (metabolite VI) was detected by h.p.l.c. and g.c. methods. This was also found in baboon plasma. 2. Metabolite VI was identified as 3'-hydroxy-4'-methoxy diclofenac by mass and n.m.r. spectroscopic analysis. Comparison with synthetic reference compound confirmed its structure. 3. In plasma, metabolite VI persists much longer than do unchanged diclofenac and the other phenolic metabolites. In urine, metabolite VI and its conjugates are excreted in trace amounts only. 4. A synthetic sample of metabolite VI was shown to be virtually inactive in animal models of inflammation and pain.

Formation of the Accumulative Human Metabolite and Human-Specific Glutathione Conjugate of Diclofenac in TK-NOG Chimeric Mice with Humanized Livers

“…In humanized chimeric mice, levels of VI in plasma reached a maximum at 8 hours and then declined with a t 1/2 of 13.0 hours. These parameters seem to be comparable to the respective values of 12 and 80 hours in humans (Faigle et al, 1988), and could be used to retrospectively predict the distinct pharmacokinetic behavior of VI in clinical practice. It had previously not been known whether VI was generated from diclofenac via II or IV as an intermediate metabolite.…”

“…Metabolite VI showed about 300 times less activity than the parent compound in inhibiting prostaglandin synthesis in vitro, and the antiinflammatory effects in vivo were very weak (Faigle et al, 1988). According to the Metabolites in Safety Testing guidance by the Food and Drug Administration and the subsequent modified guidance by the International Conference on Harmonization [ICH M3(R2); Food and Drug Administration, 2010], safety of human-specific metabolites occurring at exposure greater than 10% of total drug-related exposure should be evaluated before entering large-scale clinical trials.…”

“…While analyses on the concentrations of these metabolites in plasma samples from study subjects were performed, a new metabolite, 39-hydroxy-49-methoxydiclofenac (VI), was found. This metabolite showed distinct pharmacokinetic behavior with a time to maximum plasma concentration (T max ) and halflife (t 1/2 ) of 12 and 80 hours, respectively, after single oral administration with potential accumulation after repeated dosing of diclofenac (Degen et al, 1988;Faigle et al, 1988). According to Faigle et al (1988), unpublished data showed that VI was not found in mouse, rat, or marmoset plasma, but baboon plasma only.…”

Mitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity: current understanding and future perspectives

“…In human liver microsomes, the major oxidative metabolic pathway (the phase I reaction) of diclofenac is the formation of 4′-hydroxydiclofenac (4′-OHdic) by CYP2C9 [82, 83]. Formation of 5-hydroxydiclofenac (5-OHdic), 3′-hydroxydiclofenac, 4′,5-dihydroxydiclofenac, and 3′-hydroxy-4′-methoxydiclofenac has also been reported in humans [84, 85]. In the rat, 4′-OHdic together with 5-OHdic are the major urine metabolites [86].…”

Pharmacokinetics of Diclofenac Sodium in Chronic Active Hepatitis and Alcoholic Cirrhosis

“…Six healthy subjects, 6 chronic active hepatitis patients, and 6 alcoholic cirrhosis patients were enrolled in this prospective, open-label, parallel study. Bloodsamples were drawn at 0, 0.25, 0.5, 0.75, 1,2,4,6,8,12,24,48,72,144,312, and 480 hours, and urine samples were collected for 144 hours after administration of a single oral dose of diclofenac sodium. The mean area under the serum concentration-time curve extrapolated to infinity, oral clearance, half-life, maximal concentration, and time to peak concentration for diclofenac and its metabolites were determined and compared using analysis of variance.…”