The effect of SLCO1B1 polymorphism on repaglinide pharmacokinetics persists over a wide dose range. Br J Clin Pharmacol

Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
British Journal of Clinical Pharmacology (Impact Factor: 3.88). 10/2008; 66(6):818-25. DOI: 10.1111/j.1365-2125.2008.03287.x
Source: PubMed


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 > or =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 < 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.
The effect of SLCO1B1 c.521T-->C polymorphism on the pharmacokinetics of repaglinide persists throughout the clinically relevant dose range.

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Available from: Pertti J Neuvonen, Sep 19, 2014
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    • "The organic anion transporting polypeptide 1B1 (OATP1B1) mediates the hepatic uptake of repaglinide, where it is extensively metabolized by the cytochrome P450 isoforms CYP2C8 and CYP3A4.[4] Genetic polymorphisms of these enzymes or intake of co-medication cause significant differences in its metabolism, leading to a high inter-individual variability in pharmacokinetics and mean half-life variations of up to 45%.[5] [6] [7] Despite the inter-individual differences in elimination, the substance has generally a fairly broad therapeutic range with low risk of hypoglycemia.[8] Single doses may vary from 0.5 to 4 mg preprandially and 16 mg are defined as the recommended maximum daily dose.[9] "
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    ABSTRACT: Context: Repaglinide is a short-acting insulin secretagogue with high interindividual variability in pharmacokinetics due to genetic polymorphisms. Little is known about repaglinide overdoses, both with respect to pharmacokinetics and appropriate management. Given its short serum half-life of less than 1 h, hypoglycemic effects of repaglinide are expected to cease within a few hours post-ingestion. Case details: A 15-year-old girl ingested 10.5 mg of repaglinide in a suicide attempt. Few hours later, she developed a strong food craving, nausea, abdominal pain, and a headache. The lowest recorded serum glucose was 44 mg/dl (2.4 mmol/l) 14 h post-ingestion. Using liquid chromatography-mass spectrometry, we detected repaglinide serum levels of 5.3, 2.6, and 1.0 ng/ml at 14, 20, and 26 h post-ingestion, respectively. Discussion: This case illustrates that in the context of overdose, repaglinide can lead to prolonged hypoglycemia. We therefore recommend glucose monitoring and observation for 24 h in all patients who remain hypoglycemic or show symptoms of hypoglycemia for an unusually long period of time.
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    • "Furthermore, acyl glucuronidation has been proposed as an important metabolic pathway of repaglinide with UGT1A1 reported as the major contributing enzyme (Gan et al., 2010). The pharmacokinetics of repaglinide is further complicated by the active hepatic uptake of this drug (Ménochet et al., 2012), mediated by organic anion-transporting polypeptide (OATP) 1B1 uptake transporter (Niemi et al., 2005; Kalliokoski et al., 2008b). CYP2C8 metabolizes a wide range of drugs, showing overlapping substrate specificity with CYP3A4 (Hinton et al., 2008; Lai et al., 2009; Naraharisetti et al., 2010). "
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