Long-lasting Inhibitory Effects of Cyclosporin A, but Not Tacrolimus, on OATP1B1- and OATP1B3-mediated Uptake

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

doi:10.2133/dmpk.dmpk-11-rg-096

Cited by 81 publications

(74 citation statements)

References 31 publications

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“…As for rBsep, the initial free concentration of the liver would approximately reach the rBsep IC 50 value (1.75 mM) in the 30 mg/kg cyclosporin A group but not in the 10 mg/kg cyclosporin A group. The inhibitory effects of cyclosporin A on rat and human Oatps/OATPs were enhanced by preincubation with cyclosporin A in vitro and the inhibitory effects lasted $3 days in rats (Shitara et al, 2009(Shitara et al, , 2012Gertz et al, 2013). The in vivo result can be explained by the hypothesis that cyclosporin A has a long-lasting inhibitory effect on rBsep and rNtcp.…”

Section: Biomarkers For Inhibition Of Transportersmentioning

confidence: 95%

Utility of Bilirubins and Bile Acids as Endogenous Biomarkers for the Inhibition of Hepatic Transporters

Watanabe¹,

Miyake²,

Shimizu³

et al. 2015

Drug Metab Dispos

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It is useful to identify endogenous substrates for the evaluation of drug-drug interactions via transporters. In this study, we investigated the utility of bilirubins, substrates of OATPs and MRP2, and bile acids and substrates of NTCP and BSEP, as biomarkers for the inhibition of transporters. In rats administered 20 and 80 mg/kg rifampicin, the plasma levels of bilirubin glucuronides were elevated, gradually decreased, and almost returned to the baseline level at 24 hours after administration without an elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). This result indicates the transient inhibition of rOatps and/or rMrp2. Although the correlation between free plasma concentrations and IC 50 values of rOatps depended on the substrates used in the in vitro studies, the inhibition of rOatps by rifampicin was confirmed in the in vivo study using valsartan as a substrate of rOatps. In rats administered 10 and 30 mg/kg cyclosporin A, the plasma levels of bile acids were elevated and persisted for up to 24 hours after administration without an elevation of ALT and AST. This result indicates the continuous inhibition of rNtcp and/or rBsep, although there were differences between the free plasma or liver concentrations and IC 50 values of rNtcp or rBsep, respectively. This study suggests that the monitoring of bilirubins and bile acids in plasma is useful in evaluating the inhibitory potential of their corresponding transporters.

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Section: Biomarkers For Inhibition Of Transportersmentioning

confidence: 95%

Utility of Bilirubins and Bile Acids as Endogenous Biomarkers for the Inhibition of Hepatic Transporters

Watanabe¹,

Miyake²,

Shimizu³

et al. 2015

Drug Metab Dispos

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“…However, recently emerging information suggests that this may not be the case. For example, CsA has been shown to exhibit a long lasting inhibition on hepatic uptake of bromosulfophthalein, a probe substrate for OATPs, in rats (67), and on OATP1B1 and -1B3 mediated uptake in vitro (68,69). Conceivably, this may be a contributing factor, among several others, to the unusually high magnitude of DDIs associated with CsA.…”

Section: Transporter Data Are Dependent On In Vitro Model Systems Andmentioning

confidence: 99%

Drug–Drug Interaction Studies: Regulatory Guidance and An Industry Perspective

Prueksaritanont

Chu

Gibson

et al. 2013

AAPS J

204

154

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Abstract. Recently, the US Food and Drug Administration and European Medicines Agency have issued new guidance for industry on drug interaction studies, which outline comprehensive recommendations on a broad range of in vitro and in vivo studies to evaluate drug-drug interaction (DDI) potential. This paper aims to provide an overview of these new recommendations and an in-depth scientifically based perspective on issues surrounding some of the recommended approaches in emerging areas, particularly, transporters and complex DDIs. We present a number of theoretical considerations and several case examples to demonstrate complexities in applying (1) the proposed transporter decision trees and associated criteria for studying a broad spectrum of transporters to derive actionable information and (2) the recommended model-based approaches at an early stage of drug development to prospectively predict DDIs involving time-dependent inhibition and mixed inhibition/induction of drug metabolizing enzymes. We hope to convey the need for conducting DDI studies on a case-by-case basis using a holistic scientifically based interrogative approach and to communicate the need for additional research to fill in knowledge gaps in these areas where the science is rapidly evolving to better ensure the safety and efficacy of new therapeutic agents.

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“…The occurrence of MBI and/or longlasting inhibition of OATP2B1 with FJ has not yet been evaluated. However, it was reported that preincubation enhanced the inhibitory effect of cyclosporine A on hepatic OATP1B1-and OATP1B3-mediated drug transport, suggesting a long-lasting inhibitory effect of cyclosporine A on OATP1B1 and OATP1B3 (Amundsen et al, 2010;Shitara et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Long-Lasting Inhibitory Effect of Apple and Orange Juices, but Not Grapefruit Juice, on OATP2B1-Mediated Drug Absorption

et al. 2012

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Enzyme-based grapefruit juice (GFJ)-drug interactions are mainly due to mechanism-based irreversible inhibition of metabolizing enzyme CYP3A4 by GFJ components, but the transporter organic anion transporting polypeptide (OATP)2B1 is also a putative site of interaction between drugs and fruit juices (FJ) in the absorption process. Here we aimed to investigate the effect of preincubation with FJ on OATP2B1-mediated transport of drugs in vitro. When OATP2B1-expressing Xenopus oocytes were preincubated with GFJ, orange juice (OJ), or apple juice (AJ), AJ induced a remarkable decrease in OATP2B1-mediated estrone-3-sulfate uptake in a concentration-dependent manner (IC 50 = 1.5%). A similar but less potent effect was observed with OJ (IC 50 = 21%), whereas GFJ had no effect. Similar results were obtained in preincubation studies using fexofenadine. Preincubation with OJ and AJ resulted in timedependent inhibition of OATP2B1. Again, AJ had the more potent effect; its action lasted for at least 240 minutes, suggesting that AJ irreversibly inhibits OATP2B1-mediated drug uptake. Kinetic analysis revealed that coincubation and preincubation with AJ reduced OATP2B1-mediated estrone-3-sulfate uptake via competitive and noncompetitive mechanisms, respectively. Thus, OATP2B1 is functionally impaired through both competitive and long-lasting inhibition mechanisms by AJ and OJ, but not GFJ. Interestingly, although GFJ but not AJ is able to irreversibly inhibit CYP3A4, in the case of OATP2B1, AJ but not GFJ has a long-lasting inhibitory effect. Accordingly, complex FJ-drug interactions may occur in vivo, and their clinical significance should be examined.

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Long-lasting Inhibitory Effects of Cyclosporin A, but Not Tacrolimus, on OATP1B1- and OATP1B3-mediated Uptake

Cited by 81 publications

References 31 publications

Utility of Bilirubins and Bile Acids as Endogenous Biomarkers for the Inhibition of Hepatic Transporters

Utility of Bilirubins and Bile Acids as Endogenous Biomarkers for the Inhibition of Hepatic Transporters

Drug–Drug Interaction Studies: Regulatory Guidance and An Industry Perspective

Long-Lasting Inhibitory Effect of Apple and Orange Juices, but Not Grapefruit Juice, on OATP2B1-Mediated Drug Absorption

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