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Mechanistic studies on metabolic interactions between gemfibrozil and statins
Thomayant Prueksaritanont1, Jamie J Zhao, Bennett Ma
1Department of Drug Metabolism, WP75-100, Merck Research Laboratories, West Point, PA 19486, USA. thomayant_prueksaritanont@merck.com
Summary
Gemfibrozil (GFZ) significantly increases simvastatin hydroxy acid (SVA) exposure in dogs and humans by inhibiting SVA glucuronidation, not oxidation. This explains drug interactions between gemfibrozil and statins.
Area of Science:
- Pharmacokinetics
- Drug Metabolism
- Medicinal Chemistry
Background:
- Drug-drug interactions (DDIs) involving statins and gemfibrozil (GFZ) are clinically significant.
- Previous observations indicated increased simvastatin (SV) exposure in humans when co-administered with GFZ.
Purpose of the Study:
- To elucidate the pharmacokinetic interaction mechanism between simvastatin (SV) and gemfibrozil (GFZ).
- To investigate the impact of GFZ on SV metabolism and excretion in preclinical models and in vitro systems.
Main Methods:
- Administered SV and GFZ to dogs, measuring systemic exposure to SV and simvastatin hydroxy acid (SVA).
- Assessed ex vivo hydrolysis of SV in dog plasma and in vitro inhibition of SVA oxidation and glucuronidation by GFZ in dog and human liver microsomes.
- Studied the effect of GFZ on SVA plasma clearance and biliary excretion in dogs after intravenous SVA administration.
- Investigated the interaction of GFZ with UGT isozymes and its inhibitory effects on CYP-mediated oxidation and glucuronidation of other statins (atorvastatin, cerivastatin) in human liver microsomes.
Main Results:
- GFZ pretreatment increased systemic exposure to SVA (not SV) approximately 4-fold in dogs, mirroring human observations.
- GFZ inhibited SVA glucuronidation but had minimal effect on CYP3A-mediated SVA oxidation in vitro.
- GFZ reduced SVA plasma clearance and biliary excretion of SVA glucuronide in dogs.
- GFZ inhibited glucuronidation of both GFZ and SVA by UGT1A1 and UGT1A3.
- GFZ was a less potent inhibitor of atorvastatin oxidation than glucuronidation, but significantly inhibited cerivastatin oxidation and glucuronidation.
Conclusions:
- Gemfibrozil (GFZ) primarily interacts with simvastatin (SV) metabolism by inhibiting SVA glucuronidation, leading to increased SVA exposure.
- The findings provide metabolic insights into GFZ-statin DDIs, explaining the enhanced susceptibility of cerivastatin to these interactions.