Mechanistic Studies on Metabolic Interactions between Gemfibrozil and Statins

Abstract

A series of studies were conducted to explore the mechanism of the pharmacokinetic interaction between simvastatin (SV) and gemfibrozil (GFZ) reported recently in human subjects. After administration of a single dose of SV (4 mg/kg p.o.) to dogs pretreated with GFZ (75 mg/kg p.o., twice daily for 5 days), there was an increase (ϳ4-fold) in systemic exposure to simvastatin hydroxy acid (SVA), but not to SV, similar to the observation in humans. GFZ pretreatment did not increase the ex vivo hydrolysis of SV to SVA in dog plasma. In dog and human liver microsomes, GFZ exerted a minimal inhibitory effect on CYP3A-mediated SVA oxidation, but did inhibit SVA glucuronidation. 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. Among six human UGT isozymes tested, UGT1A1 and 1A3 were capable of catalyzing the glucuronidation of both GFZ and SVA. 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. However, with cerivastatin (CVA), the glucuronidation as well as the CYP2C8-and CYP3A4-mediated oxidation pathways were much more susceptible to inhibition by GFZ than was observed with SVA or AVA. Collectively, the results of these studies provide metabolic insight into the nature of drug-drug interaction between GFZ and statins, and a possible explanation for the enhanced susceptibility of CVA to interactions with GFZ.

Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics and pharmacodynamics of repaglinide: potentially hazardous interaction between gemfibrozil and repaglinide

“…Thus, itraconazole inhibits the CYP3A4-mediated metabolism of repaglinide, and gemfibrozil (which is not an inhibitor of CYP3A4) [7] inhibits the elimination via another pathway, probably CYP2C8 [3,4]. In addition, inhibition of glucuronidation or drug transporter could contribute to gemfibrozil interactions [8]. The correlation between the interactions of repaglinide with gemfibrozil and itraconazole might be explained by coordinate transcriptional regulation of CYP2C8 and CYP3A4.…”

Statins and Stroke

“…In addition, fibrates (i.e., nonstatin lipid-lowering drugs), especially gemfibrozil may increase statin levels partly via inhibiting the glucuronidation and subsequent biliary excretion of statins. This may be mediated via interaction with UDP-glucuronosyltransferase (Prueksaritanont et al, 2002). Therefore, concomitant use of certain interacting drugs or nutrients can increase blood levels of statins and, consequently, the risk for myopathy (Gotto, 2003;Bellosta et al, 2004;Dreier and Endres, 2004).…”

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

“…The mechanism underlying a potential pharmacokinetic interaction is not well understood. 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).…”