METABOLISM OF ACECLOFENAC IN HUMANS

Metabolism of the new nonsteroidal antiinflammatory drug aceclofenac [ 2-(2',6'-dichlorophenylamino)phenyl]acetoxyacetic acid) was investigat ed both in the in vitro hepatic human models and in vivo. Aceclofenac is metabolized in human hepatocytes and human microsomes to form ichlo ro-4'-hydroxyphenylamino)phenyl]acetoxyacetic acid as the major metabo lite, which is then further conjugated, Minor metabolites were dichlor ophenylamino)-5-hydroxyphenyl]acetoxyacetic acid and [2-(2',6'-dichlor ophenylamino)phenyl]acetic acid, as well as the hydroxylated derivativ es 2',6'-dichloro-4'-hydroxyphenylamino)phenyl]acetic acid and (2',6'- dichlorophenylamino)-5-hydroxyphenyl]acetic acid, After oral administr ation to human volunteers (100 mg, single dose), aceclofenac reached a C-max value of 7.6 +/- 1.3 mu g/ml and a t(max) of 2.6 +/- 1.8. The s ame metabolites as those detected in cell culture or microsome incubat ions were found in 12-hr urine after an oral administration of 100 mg aceclofenac to human volunteers. Cytochrome 2C9 is the enzyme responsi ble for the hydroxylation at position 4', This could be demonstrated b y: 1) selective inhibition by sulfaphenazole; 2) correlation between t he formation of the hydroxylated metabolite and tolbutamide hydroxylas e activity; and 3) formation of this metabolite only when incubated wi th microsomes obtained from cells expressing human cytochrome 2C9. How ever, no conclusive information could be obtained concerning the cytoc hrome catalyzing the hydroxylation at position 5. The comparison betwe en human microsomes and human hepatocytes metabolism on one hand, and human in vivo metabolism on the other, supports human hepatocytes in p rimary culture as the model that best anticipated the metabolism of th e drug in vivo.