Effects of the SLCO1B1*1B haplotype on the pharmacokinetics and pharmacodynamics of repaglinide and nateglinide.

OBJECTIVE

Organic anion transporting polypeptide 1B1 (OATP1B1), encoded by SLCO1B1, is an influx transporter expressed on the sinusoidal membrane of human hepatocytes. The aim of this study was to investigate whether the SLCO1B1*1B haplotype affects the pharmacokinetics and pharmacodynamics of repaglinide and nateglinide.

METHODS

Eight healthy volunteers with the SLCO1B1*1B/1B genotype and 16 with the SLCO1B11A/*1A genotype ingested a single 0.5-mg dose of repaglinide and, after a washout period of 1 week, a single 60-mg dose of nateglinide. Plasma repaglinide and nateglinide and blood glucose concentrations were measured for 7 h.

RESULTS

The AUC(0-infinity) and Cmax of repaglinide were 32% (P=0.007) and 24% lower (P=0.056) in the individuals with the SLCO1B1*1B/1B genotype than in those with the SLCO1B11A/1A genotype. The mean blood glucose concentration from 0 to 7 h after repaglinide intake was 10% higher in the SLCO1B11B/1B participants than in the SLCO1B11A/1A participants (P=0.007). The Cmax of nateglinide occurred earlier in the SLCO1B11B/1B participants than in the SLCO1B11A/*1A participants (P=0.004), but no differences were seen in the other pharmacokinetic variables of nateglinide.

CONCLUSION

The SLCO1B1*1B/*1B genotype is associated with reduced plasma concentrations of repaglinide, consistent with an enhanced hepatic uptake by OATP1B1, but has limited effects on the pharmacokinetics of nateglinide.