Long-Lasting Inhibition of the Transporter-Mediated Hepatic Uptake of Sulfobromophthalein by Cyclosporin A in Rats

Shitara, Yoshihisa; Nagamatsu, Yoshiko; Wada, S; Sugiyama, Yuichi; Horie, Toshiharu

doi:10.1124/dmd.108.025544

Cited by 59 publications

(47 citation statements)

References 34 publications

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“…A possible irreversible inhibition of OATP1B1 by CsA would potently inhibit the transporter even at low concentrations, offering an alternate explanation for the interaction observed clinically. In this respect, it is interesting to note that Shitara et al (2009) recently reported that CsA exhibited a long-lasting inhibitory effect on transporters in rat and rat hepatocytes, with a reduced IC 50 value on preincubation, in line with our findings. It is not likely that the mechanism can be explained by models from the enzyme kinetics field in which the inhibitors are required to be processed catalytically by the enzyme for inhibitory effect.…”

Section: Cyclosporine a But Not Tacrolimus Inhibits Oatp1b1supporting

confidence: 80%

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

Amundsen¹,

Christensen²,

Zabihyan³

et al. 2010

Drug Metab Dispos

127

107

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ABSTRACT:The aim of this study was to investigate the potential of calcineurin inhibitors [cyclosporine A (CsA) and tacrolimus (Tac)] to inhibit cellular uptake of atorvastatin mediated by the liver-specific organic anion-transporting polypeptide 1B1 ( The IVIVE showed that clinically obtainable concentrations of CsA, but not Tac, inhibit OATP1B1 transport of atorvastatin. CsA inhibition ranged from 28 to 77% within a dosing interval, whereas it was less than 1% for Tac, considering free concentrations and assuming competitive inhibition. This does not fully explain the clinically observed interaction with CsA, suggesting that a more complex inhibitory mechanism may be present. This is also supported by the decreased IC 50 value of CsA after preincubation. This study provides evidence that OATP1B1 inhibition is a relevant mechanism for the interaction observed between CsA and atorvastatin.

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Section: Cyclosporine a But Not Tacrolimus Inhibits Oatp1b1supporting

confidence: 80%

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

Amundsen¹,

Christensen²,

Zabihyan³

et al. 2010

Drug Metab Dispos

127

107

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“…Whereas cyclosporine A is an inhibitor of MRP2/Mrp2, it is also an inhibitor of NTCP (Mita et al, 2006), OATPs/Oatps (Shitara et al, 2009), and BSEP/Bsep (Mita et al, 2006). Accordingly, in the context of our in vitro data, cyclosporine A is likely to decrease micafungin systemic clearance by inhibiting Ntcp and/or Oatp-mediated uptake of micafungin and/or by inhibiting Bsep-mediated (and Bcrp-mediated) biliary excretion in rats.…”

Section: Discussionmentioning

confidence: 94%

In Vitro Investigation of the Hepatobiliary Disposition Mechanisms of the Antifungal Agent Micafungin in Humans and Rats

Yanni¹,

Augustijns²,

Benjamin³

et al. 2010

Drug Metab Dispos

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ABSTRACT:The purpose of the present study was to elucidate the transport mechanisms responsible for elimination of micafungin, a new semisynthetic echinocandin antifungal agent, which is predominantly cleared by biliary excretion in humans and rats. In vitro studies using sandwich-cultured rat and human hepatocytes were conducted. Micafungin uptake occurred primarily (ϳ75%) by transporter-mediated mechanisms in rat and human. Micafungin uptake into hepatocytes was inhibited by taurocholate (K i ‫؍‬ 61 M), Na

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“…Shitara et al have shown that in vivo hepatic uptake of BSP determined by the liver uptake index method was significantly decreased 3 d after administration of cyclosporine A in rats, though cyclosporine A had already been almost eliminated from the blood circulation. 39) They also observed the uptake of BSP in rat hepatocytes was also continuously decreased after preincubation with cyclosporine A and its subsequent its removal from the medium. 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.…”

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

confidence: 91%

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

Maeda

2015

Biological & Pharmaceutical Bulletin

119

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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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Long-Lasting Inhibition of the Transporter-Mediated Hepatic Uptake of Sulfobromophthalein by Cyclosporin A in Rats

Cited by 59 publications

References 34 publications

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

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

In Vitro Investigation of the Hepatobiliary Disposition Mechanisms of the Antifungal Agent Micafungin in Humans and Rats

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

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