title: Pharmacoepidemiologic and in vitro evaluation of potential drug-drug interactions of sulfonylureas with fibrates and statins.
abstract: OBJECTIVE
  To examine whether initiation of fibrates or statins in sulfonylurea users is associated with hypoglycaemia, and examine in vitro inhibition of cytochrome P450 (CYP) enzymes by statins, fenofibrate and glipizide.
  
  
  METHODS
  We used healthcare data to conduct nested case-control studies of serious hypoglycaemia (i.e. resulting in hospital admission or emergency department treatment) in persons taking glipizide or glyburide, and calculated adjusted overall and time-stratified odds ratios (ORs) and 95% confidence intervals (CIs). We also characterized the in vitro inhibition of CYP enzymes by statins, fenofibrate and glipizide using fluorometric CYP450 inhibition assays, and estimated area under the concentration-time curve ratios (AUCRs) for the drug pairs.
  
  
  RESULTS
  We found elevated adjusted overall ORs for glyburide-fenofibrate (OR 1.84, 95% CI 1.37, 2.47) and glyburide-gemfibrozil (OR 1.57, 95% CI 1.25, 1.96). The apparent risk did decline over time as might be expected from a pharmacokinetic mechanism. Fenofibrate was a potent in vitro inhibitor of CYP2C19 (IC50 = 0.2 μm) and CYP2B6 (IC50 = 0.7 μm) and a moderate inhibitor of CYP2C9 (IC50 = 9.7 μm). The predicted CYP-based AUCRs for fenofibrate-glyburide and gemfibrozil-glyburide interactions were only 1.09 and 1.04, suggesting that CYP inhibition is unlikely to explain such an interaction.
  
  
  CONCLUSIONS
  Use of fenofibrate or gemfibrozil together with glyburide was associated with elevated overall risks of serious hypoglycaemia. CYP inhibition seems unlikely to explain this observation. We speculate that a pharmacodynamic effect of fibrates (e.g. activate peroxisome proliferator-activator receptor alpha) may contribute to these apparent interactions.
authors.affiliation: Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
authors.forename: H
authors.initials: H
authors.lastname: Schelleman
authors.forename: X
authors.initials: X
authors.lastname: Han
authors.forename: C M
authors.initials: CM
authors.lastname: Brensinger
authors.forename: S K
authors.initials: SK
authors.lastname: Quinney
authors.forename: W B
authors.initials: WB
authors.lastname: Bilker
authors.forename: D A
authors.initials: DA
authors.lastname: Flockhart
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.forename: Sean
authors.initials: S
authors.lastname: Hennessy
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D016022:Case-Control Studies; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000009:adverse effects / Q000494:pharmacology; D004347:Drug Interactions; D005260:Female; D058607:Fibric Acids / Q000009:adverse effects* / Q000494:pharmacology; D005913:Glipizide / Q000009:adverse effects / Q000494:pharmacology; D005905:Glyburide / Q000009:adverse effects / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects* / Q000494:pharmacology; D007003:Hypoglycemia / Q000453:epidemiology / Q000209:etiology*; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D017891:Pharmacoepidemiology; D013453:Sulfonylurea Compounds / Q000009:adverse effects* / Q000494:pharmacology; D055815:Young Adult
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D058607:Fibric Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; D005905:Glyburide; D005913:Glipizide
keywords: cytochrome P-450 enzyme; drug-drug interactions; fibric acids; hypoglycaemia; statins; sulfonylurea compounds