The Quantitative Prediction of CYP-mediated Drug Interaction by Physiologically Based Pharmacokinetic Modeling

Kato, Motohiro; Shitara, Yoshihisa; Sato, Hitoshi; Yoshisue, Kunihiro; Hirano, Masashi; Ikeda, Toshihiko; Sugiyama, Yuichi

doi:10.1007/s11095-008-9607-2

Cited by 104 publications

(90 citation statements)

References 20 publications

(22 reference statements)

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“…Among clinically reported drug-drug interactions, most of severe cases, which cause more than a 5-fold increase in the AUC, occur by coadministration of mechanism-based inhibitors or azole antifungals, which irreversibly inhibit metabolic enzymes (Kato et al, 2008). Because CsA inhibits the hepatic uptake transporter sustainably, it may cause a severe drug-drug interaction in a clinical situation.…”

Section: Discussionmentioning

confidence: 99%

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

Shitara

Nagamatsu²,

Wada³

et al. 2009

Drug Metab Dispos

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ABSTRACT:Cyclosporin A (CsA) is a well known inhibitor of the organic aniontransporting polypeptide (OATP/Oatp) family transporters, causing a large number of transporter-mediated drug-drug interactions in clinical situations. In the present study, we examined the inhibitory effect of CsA on the hepatic uptake of sulfobromophthalein (BSP) in rats, focusing on a long-lasting inhibition. Twenty-one hours after the subcutaneous administration of CsA, the hepatic clearance of BSP was decreased. The liver uptake index study revealed that hepatic uptake of BSP was reduced in CsA-treated rats for at least 3 days. Comparison of uptake studies using isolated hepatocytes prepared from control and CsA-treated rats showed that hepatic uptake in CsA-treated rats was decreased. In primary cultured hepatocytes, after preincubation with CsA, the uptake of The inhibitory effect of CsA on the transporter-mediated uptake of BSP cannot be explained by a simple competitive mechanism and a novel mechanism should be considered.

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Section: Discussionmentioning

confidence: 99%

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

Shitara

Nagamatsu²,

Wada³

et al. 2009

Drug Metab Dispos

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“…Pharmacokinetic interactions involving cytochrome P450 enzymes have been thoroughly investigated and during the last years an increasing focus has been put on mechanism-based inhibition (Kato et al, 2008). Until now, transport prediction models have generally been based on the assumption of reversible competitive inhibition (Hinton et al, 2008).…”

Section: Cyclosporine a But Not Tacrolimus Inhibits Oatp1b1mentioning

confidence: 99%

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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“…Although PBPK models have been used for the quantitative prediction of the degree of drug-drug interaction involving metabolic enzymes (Kanamitsu et al, 2000;Ito et al, 2003;Kato et al, 2008;Zhang et al, 2009;Rowland-Yeo et al, 2010;Zhao et al, 2012) and also for describing the disposition of a drug transporter substrate pravastatin (Watanabe et al, 2009), only "static" approaches have been used for the interactions at drug transporters (Hinton et al, 2008;Yoshida et al, 2012), with no reports on the application of PBPK modeling to the best of our knowledge. In the present study, we investigated whether the increase in repaglinide AUC by ICZ and GEM can be quantitatively explained based on the clearance concept and a PBPK model incorporating the inhibition of both the hepatic uptake transporter and metabolic enzymes.…”

Section: Introductionmentioning

confidence: 99%

Analysis of the Repaglinide Concentration Increase Produced by Gemfibrozil and Itraconazole Based on the Inhibition of the Hepatic Uptake Transporter and Metabolic Enzymes

et al. 2012

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The plasma concentration of repaglinide is reported to increase greatly when given after repeated oral administration of itraconazole and gemfibrozil. The present study analyzed this interaction based on a physiologically based pharmacokinetic (PBPK) model incorporating inhibition of the hepatic uptake transporter and metabolic enzymes involved in repaglinide disposition. Firstly, the plasma concentration profiles of inhibitors (itraconazole, gemfibrozil, and gemfibrozil glucuronide) were reproduced by a PBPK model to obtain their pharmacokinetic parameters. The plasma concentration profiles of repaglinide were then analyzed by a PBPK model, together with those of the inhibitors, assuming a competitive inhibition of CYP3A4 by itraconazole, mechanism-based inhibition of CYP2C8 by gemfibrozil glucuronide, and inhibition of organic anion transporting polypeptide (OATP) 1B1 by gemfibrozil and its glucuronide. The plasma concentration profiles of repaglinide were well reproduced by the PBPK model based on the above assumptions, and the optimized values for the inhibition constants (0.0676 nM for itraconazole against CYP3A4; 14.2 mM for gemfibrozil against OATP1B1; and 5.48 mM for gemfibrozil glucuronide against OATP1B1) and the fraction of repaglinide metabolized by CYP2C8 (0.801) were consistent with the reported values. The validity of the obtained parameters was further confirmed by sensitivity analyses and by reproducing the repaglinide concentration increase produced by concomitant gemfibrozil administration at various timings/doses. The present findings suggested that the reported concentration increase of repaglinide, suggestive of synergistic effects of the coadministered inhibitors, can be quantitatively explained by the simultaneous inhibition of the multiple clearance pathways of repaglinide.

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The Quantitative Prediction of CYP-mediated Drug Interaction by Physiologically Based Pharmacokinetic Modeling

Abstract: A discrepancy between the in vivo and in vitro Ki values was observed. The prediction using in vivo Ki values and the PBPK model was more accurate than the conventional methods.

Cited by 104 publications

References 20 publications

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

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

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

Analysis of the Repaglinide Concentration Increase Produced by Gemfibrozil and Itraconazole Based on the Inhibition of the Hepatic Uptake Transporter and Metabolic Enzymes

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