BIOTRANSFORMATION OF CERIVASTATIN IN MICE, RATS, AND DOGS IN-VIVO

Biotransformation of cerivastatin was investigated in mice, rats, and dogs in vivo using the C-14-labeled drug. Marked species differences e xist, both in pathways and extent of cerivastatin metabolism. Unchange d drug, together with its lactone, predominates in dog plasma and repr esents 40% of the dose in the excreta, whereas in rat bile they accoun t for approximately 10% of the dose. In mice, the drug is metabolized rapidly and almost completely. Biotransformation of cerivastatin occur s by three distinct phase I routes and by phase II conjugation with su gar-type moieties and taurine. Phase I routes are demethylation of the pyridinyl methyl ether, beta-oxidation of the 3,5-dihydroxy acid side chain, and reductive removal of the side chain 3-hydroxy group. In do gs, demethylation is the dominating phase I biotransformation. Phase I I conjugation is equally important. In dog bile, different regioisomer ic drug glucuronides and the benzylic glucuronide and glucoside conjug ate of the demethylated drug were found. In rats, besides demethylatio n, beta-oxidation of the dihydroxy acid side chain-followed by reducti ve removal of the 5-hydroxy group-is the major reaction. The resulting pentenoic acid derivatives are observed in plasma and liver homogenat e. These metabolites are subsequently conjugated with taurine and excr eted in the bile. This metabolic sequence is also important in mice. F urthermore, only in mice, cerivastatin is subject to reductive removal of the 3-hydroxy group, together with demethylation. The 5-hydroxyhep tenoic acids formed predominate in plasma and liver homogenate, wherea s the corresponding taurine conjugates are excreted in the bile.