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Vol. 30, Issue 5, 505-512, May 2002
Department of Drug Metabolism, Merck Research Laboratories, West
Point, Pennsylvania
The active forms of all marketed hydroxymethylglutaryl
(HMG)-CoA reductase inhibitors share a common dihydroxy heptanoic or heptenoic acid side chain. In this study, we present evidence for the
formation of acyl glucuronide conjugates of the hydroxy acid forms of
simvastatin (SVA), atorvastatin (AVA), and cerivastatin (CVA) in rat,
dog, and human liver preparations in vitro and for the excretion of the
acyl glucuronide of SVA in dog bile and urine. Upon incubation of each
statin (SVA, CVA or AVA) with liver microsomal preparations
supplemented with UDP-glucuronic acid, two major products were
detected. Based on analysis by high-pressure liquid chromatography, UV
spectroscopy, and/or liquid chromatography (LC)-mass spectrometry
analysis, these metabolites were identified as a glucuronide conjugate
of the hydroxy acid form of the statin and the corresponding
-lactone. By means of an LC-NMR technique, the glucuronide structure
was established to be a
1-O-acyl-
-D-glucuronide conjugate of the
statin acid. The formation of statin glucuronide and statin lactone in
human liver microsomes exhibited modest intersubject variability (3- to
6-fold; n = 10). Studies with expressed UDP
glucuronosyltransferases (UGTs) revealed that both UGT1A1 and UGT1A3
were capable of forming the glucuronide conjugates and the
corresponding lactones for all three statins. Kinetic studies of statin
glucuronidation and lactonization in liver microsomes revealed marked
species differences in intrinsic clearance (CLint) values
for SVA (but not for AVA or CVA), with the highest CLint observed in dogs, followed by rats and humans. Of the statins studied,
SVA underwent glucuronidation and lactonization in human liver
microsomes, with the lowest CLint (0.4 µl/min/mg of
protein for SVA versus ~3 µl/min/mg of protein for AVA and CVA).
Consistent with the present in vitro findings, substantial
levels of the glucuronide conjugate (~20% of dose) and the lactone
form of SVA [simvastatin (SV); ~10% of dose] were detected in bile
following i.v. administration of [14C]SVA to dogs. The
acyl glucuronide conjugate of SVA, upon isolation from an in vitro
incubation, underwent spontaneous cyclization to SV. Since the rate of
this lactonization was high under conditions of physiological pH, the
present results suggest that the statin lactones detected previously in
bile and/or plasma following administration of SVA to animals or of AVA
or CVA to animals and humans, might originate, at least in part, from
the corresponding acyl glucuronide conjugates. Thus, acyl glucuronide
formation, which seems to be a common metabolic pathway for the hydroxy
acid forms of statins, may play an important, albeit previously
unrecognized, role in the conversion of active HMG-CoA reductase
inhibitors to their latent -lactone forms.
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