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| |  DALM: Lactone Forms Play Important Role in Drug-Drug Interactions of Statin Agents By Chris Berrie VENICE, ITALY -- October 28, 2004 -- When assessing the mechanism of action of drug-drug interactions in statins, it is important to take into account the metabolic properties and interactions of the lactone forms of these agents, according to a study presented here on October 26th at the XV International Symposium on Drugs Affecting Lipid Metabolism. Researchers recently found that glucuronidation mediated by uridine diphosphate-glucuronosyltransferase (UGT) occurs in the body. Thus, a drug such as pitavastatin, although it is administered as the acid form, turns into its acid form and lactone form in plasma, explained Hideki Fujino Catapano, PhD, chief laboratory researcher, ADME Group, Tokyo New Drug Research Laboratories I, pharmaceutical division, Kowa Company Ltd., Tokyo, Japan. Dr. Fujino and coworkers believe that this UGT-mediated process results in the formation of the very unstable ester-glucuronide form of pitavastatin, which then forms the lactone through an elimination reaction. Thus, although the statins can be administered as either prodrugs or in their active forms, the definition of glucuronidation as a novel metabolic route for statin clearance indicates the need to better understand the balance of the various metabolic pathways of the agents. In comparing the metabolic clearance of a range of statins, it was the lactone forms that were cleared primarily, Dr. Fujino said. Thus, clearance ratios of lactone:acid forms were as follows: atorvastatin, 73; rosuvastatin, 71; simvastatin, 69; cerivastatin, 30; fluvastatin, 7; pitavastatin, 2. Although the standard metabolism via the CYP3A4 P450 cytochrome was involved in the metabolism of both the acid and lactone forms of atorvastatin, simvastatin, cerivastatin, and fluvastatin, it selectively metabolised the lactone forms of rosuvastatin and pitavastatin. Similarly, while the CYP2C genes were critically involved in the metabolism of cerivastatin, fluvastatin, and pitavastatin acids, they were not involved in the metabolism of the corresponding lactones. When the metabolic inhibition of the CYP-mediated metabolism of the statins was investigated, again, there were some specific differences between these acid and lactone forms. In particular, it was the rosuvastatin lactone that was specifically able to inhibit the metabolic activities of CYP3A4 (as paclitaxel 3-hydroxylation), CYP2C8 (as paclitaxel 6-alpha-hydroxylation), and CYP2C9 (as tolbutamide 4-hydroxylation). Conversely, while the cerivastatin lactone was specific for CYP3A4, its acid form preferentially inhibited CYP2C8. Dr. Fujino said that the reasons behind the resistance of pitavastatin, in particular, against clearance relates to its structural form, whereby its lactone structure means that it remains a poor P450 substrate. Thus, this study demonstrates that the CYP-mediated metabolism of lactones can be a common metabolic pathway for statin mechanism of action, and the CYP3A4-mediated metabolic properties of the lactone forms of these agents will clearly need to be considered when assessing the mechanistic aspects of drug-drug interactions of these agents.
[Presentation title: Metabolic Properties of Acid Form and Lactone Form of HMG-CoA Reductase Inhibitors. Poster 122]
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