Cyclosporine A, but Not Tacrolimus, Shows Relevant Inhibition of Organic Anion-Transporting Protein 1B1-Mediated Transport of Atorvastatin

Amundsen, Rune; Christensen, Hege; Zabihyan, Behnaz; Åsberg, Anders

doi:10.1124/dmd.110.032268

Cited by 127 publications

(122 citation statements)

References 43 publications

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“…Instead, we confirmed that OATP1B1 and OATP1B3 were the primary transporters involved in atorvastatin uptake in vivo. The importance of OATP1B1 in hepatic atorvastatin uptake has been emphasized in other studies (Pasanen et al, 2007;Amundsen et al, 2010), but our data suggest that OATP1B3 is almost as important. The relatively high contribution of OATP1B3 to the uptake of atorvastatin differs from other statins, such as simvastatin acid and pitavastatin (Hirano et al, 2004;Elsby et al, 2012).…”

Section: Discussioncontrasting

confidence: 33%

Hepatic Uptake of Atorvastatin: Influence of Variability in Transporter Expression on Uptake Clearance and Drug-Drug Interactions

et al. 2014

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Differences in the expression and function of the organic anion transporting polypeptide (OATP) transporters contribute to interindividual variability in atorvastatin clearance. However, the importance of the bile acid transporter sodium taurocholate cotransporting polypeptide (NTCP, SLC10A1) in atorvastatin uptake clearance (CL upt ) is not yet clarified. To elucidate this issue, we investigated the relative contribution of NTCP, OATP1B1, OATP1B3, and OATP2B1 to atorvastatin CL upt in 12 human liver samples. The impact of inhibition on atorvastatin CL upt was also studied, using inhibitors of different isoform specificities. Expression levels of the four transport proteins were quantified by liquid chromatography tandem mass spectrometry. These data, together with atorvastatin in vitro kinetics, were used to predict the maximal transport activity (MTA) and interindividual differences in CL upt of each transporter in vivo. Subsequently, hepatic uptake impairment on coadministration of five clinically interacting drugs was predicted using in vitro inhibitory potencies. NTCP and OATP protein expression varied 3.7-to 32-fold among the 12 sample donors. The rank order in expression was OATP1B1 > OATP1B3 NTCP OATP2B1. NTCP was found to be of minor importance in atorvastatin disposition. Instead, OATP1B1 and OATP1B3 were confirmed as the major atorvastatin uptake transporters. The average contribution to atorvastatin uptake was OATP1B1 > OATP1B3 >> OATP2B1 > NTCP, although this rank order varied among individuals. The interindividual differences in transporter expression and CL upt resulted in marked differences in drug-drug interactions due to isoform-specific inhibition. We conclude that this variation should be considered in in vitro to in vivo extrapolations.

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Section: Discussioncontrasting

confidence: 33%

Hepatic Uptake of Atorvastatin: Influence of Variability in Transporter Expression on Uptake Clearance and Drug-Drug Interactions

et al. 2014

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“…With the assumption of competitive inhibition, the inhibition constant, K i was estimated by eq. 4 (Amundsen et al, 2010):…”

Section: Methodsmentioning

confidence: 99%

“…Effect (Amundsen et al, 2010;Shitara et al, 2013a , the cells were lysed with 0.5 ml of 0.1 N NaOH overnight at room temperature. The resulting cell lysate was neutralized with 50 ml of 1 N HCl.…”

Section: Methodsmentioning

confidence: 99%

Investigation of the Impact of Substrate Selection on In Vitro Organic Anion Transporting Polypeptide 1B1 Inhibition Profiles for the Prediction of Drug-Drug Interactions

Izumi¹,

Nozaki²,

Maeda³

et al. 2014

Drug Metab Dispos

129

139

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The risk assessment of organic anion transporting polypeptide (OATP) 1B1-mediated drug-drug interactions (DDIs) is an indispensable part of drug development. We previously reported that in vitro inhibitory potencies of several inhibitors on OATP1B1 depend on the substrates when prototypical substrates, estradiol-17b-glucuronide (E 2 G), estrone-3-sulfate, and sulfobromophthalein were used as test substrates. The purpose of this study was to comprehensively investigate this substrate-dependent inhibition of OATP1B1 using clinically relevant OATP1B1 inhibitors and substrate drugs. Effects of cyclosporine A (CsA), rifampin, and gemfibrozil on OATP1B1-mediated uptake of 12 substrate drugs were examined in OATP1B1-expressing human embryonic kidney 293 cells. The K i values (mM) for CsA varied from 0.0771 to 0.486 (6.3-fold), for rifampin from 0.358 to 1.23 (3.4-fold), and for gemfibrozil from 9.65 to 252 (26-fold). Except for the inhibition of torasemide uptake by CsA and that of nateglinide uptake by gemfibrozil, the K i values were within 2.8-fold of those obtained using E 2 G as a substrate. Preincubation potentiated the inhibitory effect of CsA on OATP1B1 with similar magnitude regardless of the substrates. R values calculated based on a static model showed some variation depending on the K i values determined with various substrates, and such variability could have an impact on the DDI predictions particularly for a weak-to-moderate inhibitor (gemfibrozil). OATP1B1 substrate drugs except for torasemide and nateglinide, or E 2 G as a surrogate, is recommended as an in vitro probe in the inhibition experiments, which will help mitigate the risk of false-negative DDI predictions potentially caused by substratedependent K i variation.

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“…Amundsen et al also demonstrated that the apparent K i value of cyclosporine A for the uptake of atorvastatin after 1-h preincubation with cyclosporine A was 1/22 of that in its coincubation. 40) Thus, it should be noted that the K i value obtained from the conventional assay may be overestimated, which leads to the underestimation of DDI risks.…”

Section: Clinical Importance Of Oatp-mediated Drug-drug Interactionsmentioning

confidence: 99%

Organic Anion Transporting Polypeptide (OATP)1B1 and OATP1B3 as Important Regulators of the Pharmacokinetics of Substrate Drugs

Maeda

2015

Biological & Pharmaceutical Bulletin

115

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Nobody doubts the importance of organic anion transporting polypeptide (OATP)1B1 and 1B3 in the clinical pharmacokinetics of substrate drugs. Based on the theory of pharmacokinetics, even if a drug is eliminated from the body by extensive metabolism, the rate-determining process of the hepatic intrinsic clearance of OATP substrates is often hepatic uptake. Because of their broad substrate specificities, once the functions of OATP1B1 or OATP1B3 are altered by several kinds of special occasions such as drug-drug interactions (DDI) and genetic polymorphisms of transporter genes, the hepatic clearance of many kinds of structurally-unrelated drugs is expected to be changed. In some cases, these alterations of pharmacokinetics lead to modified pharmacological effects and adverse reactions such as statin-induced myotoxicity and the glucose-lowering effect of anti-diabetes drugs. Thus, appropriate methods with which to quantitatively predict the changes in plasma and tissue concentrations of drugs are needed in the process of drug development. As for DDI, a static model that takes into consideration of the theoretically-maximum unbound inhibitor concentration is often used for the sensitive detection of possible DDI risks and this method has been adopted in several regulatory guidance/guidelines on DDI. Regarding genetic polymorphisms, the effects of SLCO1B1 c.388A>G and c.521T>C on the pharmacokinetics of substrate drugs have been extensively investigated. Even though there are some discrepancies, c.521T>C generally decreased hepatic uptake activity, while c.388A>G tended to slightly increase it. This article briefly summarizes the current status of research on hepatic OATP1B1 and OATP1B3 and the clinical significance of their functions.

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Cyclosporine A, but Not Tacrolimus, Shows Relevant Inhibition of Organic Anion-Transporting Protein 1B1-Mediated Transport of Atorvastatin

Cited by 127 publications

References 43 publications

Hepatic Uptake of Atorvastatin: Influence of Variability in Transporter Expression on Uptake Clearance and Drug-Drug Interactions

Hepatic Uptake of Atorvastatin: Influence of Variability in Transporter Expression on Uptake Clearance and Drug-Drug Interactions

Investigation of the Impact of Substrate Selection on In Vitro Organic Anion Transporting Polypeptide 1B1 Inhibition Profiles for the Prediction of Drug-Drug Interactions

Organic Anion Transporting Polypeptide (OATP)1B1 and OATP1B3 as Important Regulators of the Pharmacokinetics of Substrate Drugs

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