Glucuronidation of Statins in Animals and Humans: A Novel Mechanism of Statin Lactonization

Abstract

ABSTRACT: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.

Update on Statins: 2003

“…19 Although it was initially suspected that gemfibrozil increased statin levels by inhibiting CYP450 enzymes, it is now thought that its inhibition of glucuronidation of statins may be a likely culprit. 20 Gemfibrozil undergoes extensive glucuronidation by the UDP-glucuronosyltransferase (UGT) isoforms UGT1A1 and UGT1A3, which also mediate glucuronidation of statins ( Figure). Glucuronidation is now recognized as a major pathway for elimination of the active hydroxy acid metabolites of statins.…”

Clinical implications of pharmacogenomics of statin treatment

“…7,12 Pravastatin and rosuvastatin interact minimally with metabolizing enzymes, are largely excreted unchanged, and are less likely to be affected by genetic variation in metabolizing enzymes.…”

Ezetimibe-associated myopathy in monotherapy and in combination with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor

“…Competitive inhibition of the glucuronidation processes between the two drugs is a possible explanation (19,20). Both Ezetimibe-associated myopathy drugs are glucuronidated by the uridine diphosphate glycosyltransferase 1 family, polypeptide A1 enzyme (21,22). The clinical relevance of inhibition of glucuronidation remains to be established and this possibility does not explain the appearance of muscle toxicity in the patient on ezetimibe alone.…”