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Vol. 26, Issue 7, 640-652, July 1998
Departments of
Drug Metabolism and Isotope Chemistry (M.B., W.K.K.,
A.K., M.R.),
Preclinical Pharmacokinetics (W.S.), Pharma Product
Development, and
Medicinal Chemistry (R.A.), Pharma Research; and
Structural Research, Central Research (W.K.), Bayer AG
Biotransformation of cerivastatin was investigated in mice, rats,
and dogs in vivo using the 14C-labeled drug.
Marked species differences exist, both in pathways and extent of
cerivastatin metabolism. Unchanged drug, together with its lactone,
predominates in dog plasma and represents 40% of the dose in the
excreta, whereas in rat bile they account for approximately 10% of the
dose. In mice, the drug is metabolized rapidly and almost completely.
Biotransformation of cerivastatin occurs by three distinct phase I
routes and by phase II conjugation with sugar-type moieties and
taurine. Phase I routes are demethylation of the pyridinyl methyl
ether, 
-oxidation of the 3,5-dihydroxy acid side chain, and
reductive removal of the side chain 3-hydroxy group. In dogs,
demethylation is the dominating phase I biotransformation. Phase II
conjugation is equally important. In dog bile, different regioisomeric
drug glucuronides and the benzylic glucuronide and glucoside conjugate
of the demethylated drug were found. In rats, besides demethylation,
-oxidation of the dihydroxy acid side chain
followed by reductive
removal of the 5-hydroxy groupis the major reaction. The resulting
pentenoic acid derivatives are observed in plasma and liver homogenate.
These metabolites are subsequently conjugated with taurine and excreted
in the bile. This metabolic sequence is also important in mice.
Furthermore, only in mice, cerivastatin is subject to reductive removal
of the 3-hydroxy group, together with demethylation. The
5-hydroxyheptenoic acids formed predominate in plasma and liver
homogenate, whereas the corresponding taurine conjugates are excreted
in the bile.
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