High impact information on simvastatin

• Further studies conducted in human liver microsomes with atorvastatin (AVA) showed that, as with SVA, GFZ was a less potent inhibitor of the CYP3A4-mediated oxidation of this drug than its glucuronidation [1].
• In dog and human liver microsomes, GFZ exerted a minimal inhibitory effect on CYP3A-mediated SVA oxidation, but did inhibit SVA glucuronidation [1].
• Among six human UGT isozymes tested, UGT1A1 and 1A3 were capable of catalyzing the glucuronidation of both GFZ and SVA [1].
• After i.v. administration of [(14)C]SVA to dogs, GFZ treatment significantly reduced (2-3-fold) the plasma clearance of SVA and the biliary excretion of SVA glucuronide (together with its cyclization product SV), but not the excretion of a major oxidative metabolite of SVA, consistent with the in vitro findings in dogs [1].

Associations of simvastatin with other chemical compounds

• Gemfibrozil (GFZ) modestly affected the formation of beta-oxidative products and CYP3A4-mediated oxidative metabolites of simvastatin hydroxy acid (SVA) but markedly inhibited the glucuronidation-mediated lactonization of SVA and the glucuronidation of a beta-oxidation product (IC(50) approximately 50 and 15 microM, respectively) [2].

References