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Effects of Gemfibrozil and Atorvastatin on the Pharmacokinetics of Repaglinide in Relation to SLCO1B1 Polymorphism
Author(s) -
Kalliokoski A,
Backman JT,
Kurkinen KJ,
Neuvonen PJ,
Niemi M
Publication year - 2008
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2008.74
Subject(s) - repaglinide , gemfibrozil , slco1b1 , medicine , crossover study , atorvastatin , pharmacology , pharmacokinetics , fibrate , chemistry , cmax , drug interaction , endocrinology , placebo , genotype , statin , metformin , cholesterol , pharmacogenetics , biochemistry , insulin , alternative medicine , pathology , gene
In a randomized crossover study, 24 SLCO1B1 ‐genotyped healthy volunteers were given daily doses of 1,200 mg gemfibrozil, 40 mg atorvastatin, or placebo, followed by 0.25 mg of repaglinide on day 3. The mean increase in the repaglinide area under the plasma concentration–time curve from 0 h to infinity (AUC 0–∞ ) produced by gemfibrozil was larger in individuals with the SLCO1B1 c.521CC genotype ( n = 6) than in those with the c.521TC ( n = 6) and c.521TT ( n = 12) genotypes, by factors of 1.56 ( P = 0.004) and 1.54 ( P = 0.002), respectively. Gemfibrozil prolonged the repaglinide elimination half‐life 1.43 times more in the c.521CC group than in the c.521TT group ( P = 0.047), but no differences were seen in the effects on peak plasma concentration ( C max ). While on gemfibrozil, the minimum blood glucose concentration after repaglinide intake was 19% lower in the c.521CC participants than in the c.521TT participants ( P = 0.009). In the c.521TT group, atorvastatin intake had the effect of increasing repaglinide C max and AUC 0–∞ by 41% ( P = 0.001) and 18% ( P = 0.033), respectively. In conclusion, the extent of gemfibrozil–repaglinide interaction depends on SLCO1B1 genotype. Atorvastatin raises plasma repaglinide concentrations, probably by inhibiting organic anion transporting polypeptide 1B1 (OATP1B1). Clinical Pharmacology & Therapeutics (2008); 84 , 4, 488–496 doi: 10.1038/clpt.2008.74