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


METHODS
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 > or =1 week.


RESULTS
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 < or = 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.


CONCLUSIONS
The effect of SLCO1B1 c.521T-->C polymorphism on the pharmacokinetics of repaglinide persists throughout the clinically relevant dose range.
Kalliokoski
Annikka
A
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
Neuvonen
Mikko
M
Neuvonen
Pertti J
PJ
Niemi
Mikko
M
D019540:Area Under Curve; D001786:Blood Glucose / Q000235:genetics; D002219:Carbamates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D005260:Female; D005838:Genotype; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008657:Metabolic Clearance Rate; D027361:Organic Anion Transporters / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D010880:Piperidines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D055815:Young Adult
D001786:Blood Glucose; D002219:Carbamates; D007004:Hypoglycemic Agents; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D010880:Piperidines; C503999:SLCO1B1 protein, human; C072379:repaglinide