Influence of OATP1B1 Genotype on the Pharmacokinetics of Rosuvastatin in Koreans

Choi, Ji Ha; Lee, M. G.; Cho, J. Y.; Lee, J. E.; Kim, K. H.; Park, K.

doi:10.1038/sj.clpt.6100267

Cited by 113 publications

(79 citation statements)

References 34 publications

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“…These studies were conducted after administration of a single 10 mg dose of rosuvastatin. 35,36 Although there are currently no clinical reports on the effects of the 521C allele on the efficacy of rosuvastatin to lower LDL-C levels, extrapolation of the aforementioned pharmacokinetic studies would point to a reduced response. In keeping with this hypothesis, we did observe a trend toward reduced efficacy of rosuvastatin in carriers of the 521C allele, but this did not reach statistical significance (Table 2).…”

Section: Discussionmentioning

confidence: 99%

Hepatic Metabolism and Transporter Gene Variants Enhance Response to Rosuvastatin in Patients With Acute Myocardial Infarction

Bailey

Romaine

Jackson

et al. 2010

Circ Cardiovasc Genet

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on behalf of the SPACE ROCKET Trial GroupBackground-Pharmacogenetics aims to maximize benefits and minimize risks of drug treatment. Our objectives were to examine the influence of common variants of hepatic metabolism and transporter genes on the lipid-lowering response to statin therapy. Methods and Results-The Genetic Effects On STATins (GEOSTAT-1) Study was a genetic substudy of Secondary Prevention of Acute Coronary Events-Reduction of Cholesterol to Key European Targets (SPACE ROCKET) (a randomized, controlled trial comparing 40 mg of simvastatin and 10 mg of rosuvastatin) that recruited 601 patients after myocardial infarction. We genotyped the following functional single nucleotide polymorphisms in the genes coding for the cytochrome P450 (CYP) metabolic enzymes, CYP2C9*2 (430CϾT), CYP2C9*3 (1075AϾC), CYP2C19*2 (681GϾA), CYP3A5*1 (6986AϾG), and hepatic influx and efflux transporters SLCO1B1 (521TϾC) and breast cancer resistance protein (BCRP; 421CϾA). We assessed 3-month LDL cholesterol levels and the proportion of patients reaching the current LDL cholesterol target of Ͻ70 mg/dL (Ͻ1.81 mmol/L). An enhanced response to rosuvastatin was seen for patients with variant genotypes of either CYP3A5 (Pϭ0.006) or BCRP (Pϭ0.010). Furthermore, multivariate logistic-regression analysis revealed that patients with at least 1 variant CYP3A5 and/or BCRP allele (nϭ186) were more likely to achieve the LDL cholesterol target (odds ratio: 2.289; 95% CI: 1.157, 4.527; Pϭ0.017; rosuvastatin 54.0% to target vs simvastatin 33.7%). There were no differences for patients with variants of CYP2C9, CYP2C19, or SLCO1B1 in comparison with their respective wild types, nor were differential effects on statin response seen for patients with the most common genotypes for CYP3A5 and BCRP (nϭ415; odds ratio: 1.207; 95% CI: 0.768, 1.899; Pϭ0.415). Conclusion-The

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Section: Discussionmentioning

confidence: 99%

Hepatic Metabolism and Transporter Gene Variants Enhance Response to Rosuvastatin in Patients With Acute Myocardial Infarction

Bailey

Romaine

Jackson

et al. 2010

Circ Cardiovasc Genet

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“…For example, cyclosporine A significantly increased systemic exposures of cerivastatin (1) and repaglinide (3) by inhibiting OATP1B1-mediated hepatic uptake (2). Genetic polymorphism of OATP1B1 (96-100) caused variation in the pharmacokinetics in human for many drugs such as fexofenadine (101), pitavastatin (102,103), pravastatin (104-110), repaglinide (111,112), rosuvastatin (113), temocapril (109), and valsartan (109). Although these data strongly suggest that the transporters are involved in the elimination process of drugs as much as the pharmacokinetics are affected by the perturbations of transporter activities, the quantitative prediction of overall intrinsic clearance (CL int,all in Eq.…”

Section: Prediction Of Tarnsporter-mediated Hepatic Uptake Clearance mentioning

confidence: 99%

Prediction of Hepatic Clearance in Human From In Vitro Data for Successful Drug Development

Chiba

Ishii²,

Sugiyama

2009

AAPS J

194

168

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Abstract. The in vivo metabolic clearance in human has been successfully predicted by using in vitro data of metabolic stability in cryopreserved preparations of human hepatocytes. In the predictions by human hepatocytes, the systematic underpredictions of in vivo clearance have been commonly observed among different datasets. The regression-based scaling factor for the in vitro-to-in vivo extrapolation has mitigated discrepancy between in vitro prediction and in vivo observation. In addition to the elimination by metabolic degradation, the important roles of transporter-mediated hepatic uptake and canalicular excretion have been increasingly recognized as a rate-determining step in the hepatic clearance. It has been, therefore, proposed that the in vitro assessment should allow the evaluation of clearances for both transporter(s)-mediated uptake/excretion and metabolic degradation. This review first outlines the limited ability of subcellular fractions such as liver microsomes to predict hepatic clearance in vivo. It highlights the advantages of cryopreserved human hepatocytes as one of the versatile in vitro systems for the prediction of in vivo metabolic clearance in human at the early development stage. The following section discusses the mechanisms underlying the systematic underprediction of in vivo intrinsic clearance by hepatocytes. It leads to the proposal for the assessment of hepatic uptake clearance as one of the kinetically important determinants for accurate predictions of hepatic clearance in human. The judicious combination of advanced technologies and understandings for the drug disposition allows us to rationally optimize new chemical entities to the drug candidate with higher probability of success during the clinical development.

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“…However, for drugs that have a target inside the liver, decreased hepatic uptake by OATP1B1*15 might result in decreased pharmacological response and give rise to unforeseen toxic side effects. Indeed, it has been demonstrated that patients carrying the OATP1B1*15 variant show markedly increased plasma levels, decreased pharmacological response, and even increased extrahepatic toxicity, for instance, after pravastatin, pitavastatin, or rosuvastatin treatment (Niemi et al, 2004;Chung et al, 2005;Igel et al, 2006;Choi et al, 2008;Fahrmayr et al, 2010;Niemi et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Drug-Drug Interactions between Rosuvastatin and Oral Antidiabetic Drugs Occurring at the Level of OATP1B1

Steeg

Greupink

Schreurs

et al. 2013

Drug Metabolism and Disposition

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Organic anion-transporting polypeptide 1B1 (OATP1B1) is an important hepatic uptake transporter, of which the polymorphic variant OATP1B1*15 (Asn130Asp and Val174Ala) has been associated with decreased transport activity. Rosuvastatin is an OATP1B1 substrate and often concomitantly prescribed with oral antidiabetics in the clinic. The aim of this study was to investigate possible drug-drug interactions between these drugs at the level of OATP1B1 and OATP1B1*15. We generated human embryonic kidney (HEK)293 cells stably overexpressing OATP1B1 or OATP1B1*15 that showed similar protein expression levels of OATP1B1 and OATP1B1*15 at the cell membrane as measured by liquid chromatography-tandem mass spectrometry. In HEK-OATP1B1*15 cells, the V max for OATP1B1-mediated transport of E 2 17b-G (estradiol 17b-D-glucuronide) was decreased >60%, whereas K m values (Michaelis constant) were comparable. Uptake of rosuvastatin in HEK-OATP1B1 cells (K m 13.1 6 0.43 mM) was nearly absent in HEK-OATP1B1*15 cells. Interestingly, several oral antidiabetics (glyburide, glimepiride, troglitazone, pioglitazone, glipizide, gliclazide, and tolbutamide), but not metformin, were identified as significant inhibitors of the OATP1B1-mediated transport of rosuvastatin. The IC 50 values for inhibition of E 2 17b-G uptake were similar between OATP1B1 and OATP1B1*15. In conclusion, these studies indicate that several oral antidiabetic drugs affect the OATP1B1-mediated uptake of rosuvastatin in vitro. The next step will be to translate these data to the clinical situation, as it remains to be established whether the studied oral antidiabetics indeed affect the clinical pharmacokinetic profile of rosuvastatin in patients.

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Influence of OATP1B1 Genotype on the Pharmacokinetics of Rosuvastatin in Koreans

Cited by 113 publications

References 34 publications

Hepatic Metabolism and Transporter Gene Variants Enhance Response to Rosuvastatin in Patients With Acute Myocardial Infarction

Hepatic Metabolism and Transporter Gene Variants Enhance Response to Rosuvastatin in Patients With Acute Myocardial Infarction

Prediction of Hepatic Clearance in Human From In Vitro Data for Successful Drug Development

Drug-Drug Interactions between Rosuvastatin and Oral Antidiabetic Drugs Occurring at the Level of OATP1B1

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