title: Effects of gemfibrozil and atorvastatin on the pharmacokinetics of repaglinide in relation to SLCO1B1 polymorphism.
abstract: In a randomized crossover study, 24 SLCO181-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-infinity)) 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.521 CC 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 Cmax and AUC(0-infinity) by41% (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).
authors.affiliation: Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: A
authors.initials: A
authors.lastname: Kalliokoski
authors.forename: J T
authors.initials: JT
authors.lastname: Backman
authors.forename: K J
authors.initials: KJ
authors.lastname: Kurkinen
authors.forename: P J
authors.initials: PJ
authors.lastname: Neuvonen
authors.forename: M
authors.initials: M
authors.lastname: Niemi
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D000069059:Atorvastatin; D001786:Blood Glucose / Q000032:analysis; D002219:Carbamates / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004347:Drug Interactions; D005260:Female; D015248:Gemfibrozil / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D005838:Genotype; D006207:Half-Life; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D027361:Organic Anion Transporters / Q000235:genetics* / Q000378:metabolism; D010880:Piperidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011110:Polymorphism, Genetic; D011758:Pyrroles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D001786:Blood Glucose; D002219:Carbamates; D006538:Heptanoic Acids; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D010880:Piperidines; D011758:Pyrroles; C503999:SLCO1B1 protein, human; C072379:repaglinide; D000069059:Atorvastatin; D015248:Gemfibrozil