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Vol. 303, Issue 3, 969-978, December 2002
Department of Drug Metabolism, Merck Research Laboratories, Rahway,
New Jersey
Diclofenac is eliminated predominantly (~50%) as its 4'-hydroxylated
metabolite in humans, whereas the acyl glucuronide (AG) pathway appears
more important in rats (~50%) and dogs (>80-90%). However,
previous studies of diclofenac oxidative metabolism in human liver
microsomes (HLMs) have yielded pronounced underprediction of human in
vivo clearance. We determined the relative quantitative importance of
4'-hydroxy and AG pathways of diclofenac metabolism in rat, dog, and
human liver microsomes. Microsomal intrinsic clearance values
(CLint = Vmax/Km) were
determined and used to extrapolate the in vivo blood clearance of
diclofenac in these species. Clearance of diclofenac was accurately
predicted from microsomal data only when both the AG and the 4'-hydroxy
pathways were considered. However, the fact that the AG pathway in HLMs accounted for ~75% of the estimated hepatic CLint of
diclofenac is apparently inconsistent with the 4'-hydroxy diclofenac
excretion data in humans. Interestingly, upon incubation with HLMs,
significant oxidative metabolism of diclofenac AG, directly to
4'-hydroxy diclofenac AG, was observed. The estimated hepatic
CLint of this pathway suggested that a significant fraction
of the intrahepatically formed diclofenac AG may be converted to its
4'-hydroxy derivative in vivo. Further experiments indicated that this
novel oxidative reaction was catalyzed by CYP2C8, as opposed to
CYP2C9-catalyzed 4'-hydroxylation of diclofenac. These findings may
have general implications in the use of total (free + conjugated)
oxidative metabolite excretion for determining primary routes of drug
clearance and may question the utility of diclofenac as a probe for
phenotyping human CYP2C9 activity in vivo via measurement of its
pharmacokinetics and total 4'-hydroxy diclofenac urinary excretion.
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