Comparative metabolism of the nonsteroidal antiinflammatory drug, aceclofenac, in the rat, monkey, and human.
Aceclofenac ([2-(2',6'-dichlorophenylamino)phenyl]acetoxyacetic acid) is a novel nonsteroidal antiinflammatory drug, the pharmacokinetics and drug metabolism of which show species differences. After oral administration to the rat, circulating aceclofenac rapidly disappears yielding [2-(2',6'-dichlorophenylamino)phenyl]acetic acid (diclofenac), which is then further oxidized to [2-(2',6'-dichloro-4'-hydroxyphenylamino)phenyl[acetic acid (4'-hydroxydiclofenac) and [2-(2',6'-dichloro-4'-hydroxyphenylamino)phenyl]acetic acid (4'-hydroxydiclofenac) and [2-(2',6'-dichlorophenylamino)-5-hydroxyphenyl]acetic acid (5-hydroxydiclofenac). This is a minor route in humans, wherein aceclofenac is hydroxylated to [2-(2',6'-dichloro-4'-hydroxyphenylamino)phenyl]acetoxyacetic acid (4'-hydroxyaceclofenac), which becomes the major metabolite. In the monkey, the conversion of aceclofenac to diclofenac takes place, but to a much lesser extent than in the rat, and the 4'-hydroxylated metabolites from both compounds are found in monkeys' urine. The mechanistic basis for this species-dependent variations seems to be the different stability of the drug toward liver esterases. In the rat, the most efficient aceclofenac-hydrolyzing activity is found in hepatic microsomes (Vmax = 2113 +/- 177 pmol/min/mg protein and KM = 191 +/- 40 microM) and cytosol (Vmax = 479 +/- 37 pmol/min/mg protein and KM = 75 +/- 22 microM). Consequently, incubation of aceclofenac with cultured rat hepatocytes or in the rat in vivo results in a rapid hydrolysis of the drug, followed by oxidative metabolism of the resulting diclofenac, yielding 4'- and 5-hydroxylated derivatives as the major metabolites. In contrast, the aceclofenac ester bond is much more stable toward human hepatic microsomal (Vmax = 27 +/- 10 pmol/min/mg protein and KM = 792 +/- 498 microM) and cytosolic (Vmax = 87 +/- 5 pmol/min/mg protein and KM 218 +/- 30 microM) esterases, and 4'-hydroxyaceclofenac becomes the major metabolite in cultured human hepatocytes, as well as in human urine. The research presented herein also illustrates the suitability of cultured human hepatocytes for predicting aceclofenac metabolism in humans.
Bort
R
R
Unidad de Hepatología Experimental, Hospital Universitario La Fe, Valencia, Spain.
Ponsoda
X
X
Carrasco
E
E
Gómez-Lechón
M J
MJ
Castell
J V
JV
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism*; D002478:Cells, Cultured; D003600:Cytosol / Q000201:enzymology; D004008:Diclofenac / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D004950:Esterases / Q000378:metabolism; D005260:Female; D006207:Half-Life; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008252:Macaca fascicularis; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D051381:Rats; D013045:Species Specificity
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004008:Diclofenac; D004950:Esterases; C056498:aceclofenac