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Vol. 301, Issue 3, 1042-1051, June 2002
Department of Drug Metabolism, Merck Research Laboratories, West
Point, Pennsylvania
A series of studies were conducted to explore the mechanism of
the pharmacokinetic interaction between simvastatin (SV) and gemfibrozil (GFZ) reported recently in human subjects. After
administration of a single dose of SV (4 mg/kg p.o.) to dogs pretreated
with GFZ (75 mg/kg p.o., twice daily for 5 days), there was an increase (~4-fold) in systemic exposure to simvastatin hydroxy acid (SVA), but
not to SV, similar to the observation in humans. GFZ pretreatment did
not increase the ex vivo hydrolysis of SV to SVA in dog plasma. In dog
and human liver microsomes, GFZ exerted a minimal inhibitory effect on
CYP3A-mediated SVA oxidation, but did inhibit SVA glucuronidation. After i.v. administration of [14C]SVA to dogs, GFZ
treatment significantly reduced (2-3-fold) the plasma clearance of SVA
and the biliary excretion of SVA glucuronide (together with its
cyclization product SV), but not the excretion of a major oxidative
metabolite of SVA, consistent with the in vitro findings in dogs. Among
six human UGT isozymes tested, UGT1A1 and 1A3 were capable of
catalyzing the glucuronidation of both GFZ and SVA. Further studies
conducted in human liver microsomes with atorvastatin (AVA) showed
that, as with SVA, GFZ was a less potent inhibitor of the
CYP3A4-mediated oxidation of this drug than its glucuronidation.
However, with cerivastatin (CVA), the glucuronidation as well as the
CYP2C8- and CYP3A4-mediated oxidation pathways were much more
susceptible to inhibition by GFZ than was observed with SVA or AVA.
Collectively, the results of these studies provide metabolic insight
into the nature of drug-drug interaction between GFZ and statins, and a
possible explanation for the enhanced susceptibility of CVA to
interactions with GFZ.
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