The effect of SLCO1B1 polymorphism on repaglinide pharmacokinetics persists over a wide dose range

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT center dot Organic anion transporting polypeptide 1B1 is an influx transporter expressed on the basolateral membrane of hepatocytes. center dot A common single nucleotide polymorphism, c.521T -> C (p.Val174Ala), of the SLCO1B1 gene has been associated with increased plasma repaglinide concentrations in healthy volunteers. center dot Previous studies at low repaglinide doses have suggested that the effect of SLCO1B1 c.521T -> C polymorphism on the pharmacokinetics of repaglinide could be dose-dependent. WHAT THIS STUDY ADDS center dot Repaglinide peak plasma concentration and area under the plasma concentration-time curve increased linearly along with repaglinide dose ranging from 0.25 to 2 mg in both the predominant c.521TT and rare c.521CC genotype group. center dot The effect of SLCO1B1 c.521T -> C polymorphism on repaglinide pharmacokinetics persists over a wide dose range. To establish whether the effect of SLCO1B1 [encoding organic anion transporting polypeptide 1B1 (OATP1B1)] c.521T -> C (p.Val174Ala) polymorphism on the pharmacokinetics of repaglinide is dose-dependent. Twelve healthy volunteers with the SLCO1B1 c.521TT genotype (controls) and eight with the c.521CC genotype ingested a single 0.25-, 0.5-, 1- or 2-mg dose of repaglinide in a dose-escalation study with a wash-out period of >= 1 week. The mean area under the plasma concentration-time curve from time 0 to infinity (AUC(0-infinity)) of 0.25, 0.5, 1 or 2 mg repaglinide was 82% (95% confidence interval 47, 125), 72% (24, 138), 56% (24, 95) or 108% (59, 171) (P <= 0.001) larger in participants with the SLCO1B1 c.521CC genotype than in those with the c.521TT genotype, respectively. Repaglinide peak plasma concentration and AUC(0-infinity) increased linearly along with repaglinide dose in both genotype groups (r > 0.88, P < 0.001). There was a tendency towards lower blood glucose concentrations after repaglinide administration in the participants with the c.521CC genotype than in those with the c.521TT genotype. The effect of SLCO1B1 c.521T -> C polymorphism on the pharmacokinetics of repaglinide persists throughout the clinically relevant dose range.