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
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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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    • "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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    ABSTRACT: Repaglinide is presently recommended by the U.S. Food and Drug Administration as a clinical CYP2C8 probe, yet current in vitro and clinical data are inconsistent concerning the role of this enzyme in repaglinide elimination. The aim of the current study was to perform a comprehensive investigation of repaglinide metabolic pathways and assess their contribution to the overall clearance. Formation of four repaglinide metabolites was characterized using in vitro systems with differential complexity. Full kinetic profiles for the formation of M1, M2, M4, and repaglinide glucuronide were obtained in pooled cryopreserved human hepatocytes, human liver microsomes, human S9 fractions, and recombinant cytochrome P450 enzymes. Distinct differences in clearance ratios were observed between CYP3A4 and CYP2C8 for M1 and M4 formation, resulting in a 60-fold M1/M4 ratio in recombinant (r) CYP3A4, in contrast to 0.05 in rCYP2C8. Unbound K(m) values were within 2-fold for each metabolite across all in vitro systems investigated. A major system difference was seen in clearances for the formation of M2, which is suggested to be a main metabolite of repaglinide in vivo. An approximately 7-fold higher unbound intrinsic clearance was observed in hepatocytes and S9 fractions in comparison to microsomes; the involvement of aldehyde dehydrogenase in M2 formation was shown for the first time. This systematic analysis revealed a comparable in vitro contribution from CYP2C8 and CYP3A4 to the metabolism of repaglinide (<50%), whereas the contribution of glucuronidation ranged from 2 to 20%, depending on the in vitro system used. The repaglinide M4 metabolic pathway is proposed as a specific CYP2C8 probe for the assessment of drug-drug interactions.
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    ABSTRACT: Drug uptake transporters are now increasingly recognized as clinically relevant determinants of variable drug responsiveness and unexpected drug-drug interactions. Emerging evidence strongly suggests members of the organic anion transporting polypeptide (OATP) family appear to be particularly important to the disposition of many drugs in clinical use today. Specifically, the liver-enriched OATP1B subfamily members OATP1B1 and OATP1B3 exhibit broad substrate specificity and the ability to transport drugs which are ligands for xenobiotic sensing nuclear receptors such as the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR). Accordingly, OATP1B transporters may indirectly regulate expression of drug metabolism genes via modulation of the intracellular concentration of PXR and CAR ligands. Moreover, a number of functionally important single nucleotide polymorphisms (SNPs) in OATP1B transporters have been described. In this review, a brief summary of known SNPs in PXR and CAR will be followed by an in-depth outline of OATP1B1 and OATP1B3 transporters particularly in relation to the known SNPs in these OATPs and the interplay between OATP1B transporters with PXR and CAR, both in vitro and in vivo.
    Molecular Pharmaceutics 07/2009; 6(6):1644-61. DOI:10.1021/mp9000298 · 4.38 Impact Factor
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    ABSTRACT: Membrane transporters are now recognized as important determinants of the transmembrane passage of drugs. Organic anion transporting polypeptides (OATP) form a family of influx transporters expressed in various tissues important for pharmacokinetics. Of the 11 human OATP transporters, OATP1B1, OATP1B3 and OATP2B1 are expressed on the sinusoidal membrane of hepatocytes and can facilitate the liver uptake of their substrate drugs. OATP1A2 is expressed on the luminal membrane of small intestinal enterocytes and at the blood-brain barrier, potentially mediating drug transport at these sites. Several clinically used drugs have been identified as substrates of OATP transporters (e.g. many statins are substrates of OATP1B1). Some drugs may inhibit OATP transporters (e.g. cyclosporine) causing pharmacokinetic drug-drug interactions. Moreover, genetic variability in genes encoding OATP transporters can result in marked inter-individual differences in pharmacokinetics. For example, a single nucleotide polymorphism (c.521T > C, p.Val174Ala) in the SLCO1B1 gene encoding OATP1B1 decreases the ability of OATP1B1 to transport active simvastatin acid from portal circulation into the liver, resulting in markedly increased plasma concentrations of simvastatin acid and an enhanced risk of simvastatin-induced myopathy. SLCO1B1 polymorphism also affects the pharmacokinetics of many other, but not all (fluvastatin), statins and that of the antidiabetic drug repaglinide, the antihistamine fexofenadine and the endothelin A receptor antagonist atrasentan. This review compiles the current knowledge about the expression and function of human OATP transporters, their substrate and inhibitor specificities, as well as pharmacogenetics.
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