Polymorphic organic anion transporting polypeptide 1B1 is a major determinant of repaglinide pharmacokinetics.
OBJECTIVE
A large interindividual variability exists in the plasma concentrations of repaglinide. Our aim was to investigate possible associations between the pharmacokinetics of repaglinide and single nucleotide polymorphisms (SNPs) in the genes encoding for the drug transporters organic anion transporting polypeptide 1B1 (OATP1B1) (SLCO1B1 ) and P-glycoprotein ( MDR1 , ABCB1 ) and the drug-metabolizing enzymes cytochrome P450 (CYP) 2C8 and CYP3A5.


METHODS
A total of 56 healthy volunteers ingested a single 0.25-mg dose of repaglinide. Plasma repaglinide and blood glucose concentrations were measured for up to 7 hours. All subjects were genotyped for the -11187G>A and 521T>C SNPs in SLCO1B1 and the 3435C>T and 2677G>T/A SNPs in ABCB1 , as well as for the CYP2C8*3 (416G>A, 1196A>G), CYP2C8*4 (792C>G), and CYP3A5*3 (6986A>G) alleles.


RESULTS
The area under the plasma concentration-time curve from time 0 to infinity [AUC(0-infinity)] and peak concentration in plasma (Cmax) of repaglinide varied 16.9-fold and 10.7-fold, respectively, between individual subjects. Multiple regression analyses indicated that the SLCO1B1 521T>C SNP and the CYP2C8*3 allele were independent predictors of the AUC(0-infinity) and Cmax of repaglinide (adjusted multiple R2 = 45% and 36%, respectively). In subjects with the SLCO1B1 521CC genotype, the AUC(0-infinity) of repaglinide was 107% and 188% higher, respectively, than in subjects with the SLCO1B1 521TC or 521TT (reference) genotype (P < .0001). In subjects with the CYP2C8*1/*3 genotype, the AUC(0-infinity) and Cmax of repaglinide were 48% and 44% lower, respectively, than in those with the CYP2C8*1/*1 genotype (P < .05). The pharmacokinetics of repaglinide was not associated with the studied ABCB1 SNPs or the CYP3A5*3 allele. The elimination half-life of repaglinide was not associated with any SNP. Only the SLCO1B1 -11187GA genotype was significantly associated with an enhanced effect of repaglinide on blood glucose.


CONCLUSIONS
Genetic polymorphism in SLCO1B1 is a major determinant of interindividual variability in the pharmacokinetics of repaglinide. The effect of SLCO1B1 polymorphism on the pharmacokinetics of repaglinide may be clinically important.
Niemi
Mikko
M
Department of Clinical Pharmacology, University of Helsinki University Central Hospital, Helsinki. mikko.niemi@hus.fi
Backman
Janne T
JT
Kajosaari
Lauri I
LI
Leathart
Julian B
JB
Neuvonen
Mikko
M
Daly
Ann K
AK
Eichelbaum
Michel
M
Kivistö
Kari T
KT
Neuvonen
Pertti J
PJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D002219:Carbamates / Q000493:pharmacokinetics*; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D019450:Genes, MDR; D005838:Genotype; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics*; D027381:Liver-Specific Organic Anion Transporter 1 / Q000235:genetics*; D008297:Male; D010880:Piperidines / Q000493:pharmacokinetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D002219:Carbamates; D007004:Hypoglycemic Agents; D027381:Liver-Specific Organic Anion Transporter 1; D010880:Piperidines; C072379:repaglinide; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A