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The effect of SLCO1B1 polymorphism on repaglinide pharmacokinetics persists over a wide dose range
Author(s) -
Kalliokoski Annikka,
Neuvonen Mikko,
Neuvonen Pertti J.,
Niemi Mikko
Publication year - 2008
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2008.03287.x
Subject(s) - repaglinide , slco1b1 , pharmacokinetics , organic anion transporting polypeptide , pharmacology , genotype , medicine , chemistry , plasma concentration , transporter , single nucleotide polymorphism , biochemistry , gene , metformin , insulin
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Organic anion transporting polypeptide 1B1 is an influx transporter expressed on the basolateral membrane of hepatocytes. • 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. • 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 • 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. • The effect of SLCO1B1 c.521T→C polymorphism on repaglinide pharmacokinetics persists over a wide dose range. AIMS 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 ≥1 week. RESULTS The mean area under the plasma concentration–time curve from time 0 to infinity (AUC 0–∞ ) 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–∞ 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.