Quantitative Prediction of OATP-Mediated Disposition and Biliary Clearance Using Human Liver Chimeric Mice

Miyake, Taiji; Tsutsui, Hironori; Hirabayashi, Manabu; Tachibana, Tatsuhiko

doi:10.1124/jpet.123.001595

Cited by 3 publications

(5 citation statements)

References 56 publications

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“…In conclusion, the paper by Miyake et al (2023) provides strong data that support the use of a humanized mouse liver model for characterization of the role of OATP transporters in determining drug disposition and the potential for drug-drug interactions in humans. Clear strengths of the work include the use of a large number of clinically important drugs whose liver transport is largely mediated by OATPs, the methodical approaches taken to presenting the calculations, and a careful consideration of variability factors and potential issues with the humanized mouse model.…”

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confidence: 78%

“…A major issue in the inclusion of OATP assessments is what preclinical model to use to determine OATP transporter function and the potential for drug-drug-interactions that will be relevant to humans. The paper by Miyake and colleagues (Miyake et al, 2023) from this issue of JPET that is highlighted in this viewpoint directly addresses this critical issue by presenting and validating a novel humanized or chimeric mouse model to evaluate OATP-mediated transport and biliary clearance of a broad range of drugs and transporter substrates.…”

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confidence: 99%

“…The highlighted article by Miyake et al (2023) is the first study to comprehensively demonstrate that human OATP-mediated clearance and drug-drug-interactions can be quantitatively predicted using a human liver chimeric mouse model. Further, these authors evaluated the accuracy of measuring biliary clearance of a large array of drugs that are OATP substrates in these mice for predicting results in human liver.…”

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confidence: 99%

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A Novel Approach to Predicting Organic Anion Transporting Polypeptide Function in Human Hepatic Drug Disposition and Biliary Clearance

Lash

2023

J Pharmacol Exp Ther

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The transport of drugs into and out of the liver plays a critical role in determining drug disposition and therapeutic efficacy. Competition between drugs or inhibition of transporter function also makes membrane transporters an important site for drug-drug-interactions that can impact therapeutic efficacy and the likelihood of adverse effects. Among the numerous plasma membrane carrier proteins found in the liver, the organic anion transporting polypeptide (OATP; SLCO gene family) transporters are among the most important for many anionic drugs and amphiphilic substrates, including cancer chemotherapeutic agents (Kalliokoski and Niemi, 2009;Tu et al., 2013;van de Steeg et al., 2013). The OATP or SLCO gene family of transporters comprises 11 individual carrier proteins in humans (https://www.guidetopharmacology.org/ GRAC/FamilyDisplayForward?familyId=238). These carriers are further divided into 6 families and 10 subfamilies based on amino acid sequence. While they all have in common the properties of 12 transmembrane domains with intracellular termini, multiple glycosylation sites, and the mediation of sodium-independent uptake of various amphiphilic substrates, the different carriers have distinct tissue localizations. There are six OATP proteins that are expressed in the liver, including SLCO1A2, SLCO2A1, and SLCO2B1 (ubiquitously expressed), SLCO1B1 and SLCO1B3 (selectively expressed in the liver), and SLCO4A1 (expressed in the liver as well as the heart, placenta, and lung).

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confidence: 78%

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confidence: 99%

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confidence: 99%

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A Novel Approach to Predicting Organic Anion Transporting Polypeptide Function in Human Hepatic Drug Disposition and Biliary Clearance

Lash

2023

J Pharmacol Exp Ther

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“…For that reason, we used male Hu-PXB mice to minimize the remaining murine effect in the present study. On the other hand, Hu-PXB mice have the ability to reflect the drug disposition of their hepatocyte donor (Miyake et al, 2023). This means the performance of Hu-PXB mice may vary depending on the donor of primary human hepatocyte.…”

Section: Discussionmentioning

confidence: 99%

“…There are numerous publications not only on the metabolism of the chimeric mice but also on their transporters (Feng et al, 2021;Miyake et al, 2023;Sanoh et al, 2020;Takehara et al, 2019;Uchida et al, 2018). However, there are few extrapolation studies in DDI using the chimeric mice that consider the contribution of both enzymes and transporters.…”

Section: Introductionmentioning

confidence: 99%

Quantitative prediction of CYP3A‐mediated drug–drug interactions by correctly estimating fraction metabolized using human liver chimeric mice

Miyake,

Mochizuki,

Nakagawa

et al. 2023

British J Pharmacology

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Background and PurposeFraction metabolized (fm) and fraction transported (ft) are important for understanding drug‐drug interactions (DDIs) in drug discovery and development. However, current in vitro systems cannot accurately estimate in vivo fm due to inability to reflect the ft by efflux transporter (ft,efflux). This study demonstrates how CYP3A‐mediated DDI for CYP3A/P‐gp substrates can be predicted using Hu‐PXB mice as human liver chimeric mice.Experimental ApproachFor estimating human in vitro fm by CYP3A enzyme (fm,CYP3A,in vitro), six drugs including CYP3A/P‐gp substrates (alprazolam, cyclosporine, docetaxel, midazolam, prednisolone, and theophylline) and human hepatocytes were incubated with or without ketoconazole as a CYP3A inhibitor. We calculated fm,CYP3A,in vitro based on hepatic intrinsic clearance. To estimate human in vivo fm,CYP3A (fm,CYP3A,in vivo), we collected information on clinical DDI caused by ketoconazole for these six drugs. We calculated fm,CYP3A,in vivo using the change of total clearance (CLtotal). For evaluating the human DDI predictability, the six drugs were administered intravenously to Hu‐PXB and SCID mice with or without ketoconazole. We calculated the change of CLtotal caused by ketoconazole. We compared the CLtotal change in humans with that in Hu‐PXB and SCID mice.Key ResultsThe fm,CYP3A,in vitro was overestimated compared to the fm,CYP3A,in vivo. Hu‐PXB mice showed much better correlation in the change of CLtotal with humans (R2 = 0.95) compared to SCID mice (R2 = 0.0058).Conclusions and ImplicationsCYP3A‐mediated DDI can be predicted by correctly estimating human fm,CYP3A,in vivo using Hu‐PXB mice. These mice could be a useful tool for predicting hepatic fm and ft,efflux.

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Empirical scaling factor for predicting human pharmacokinetic profiles of disproportionate metabolites using the Css–MRTpo method and chimeric mice with humanised livers

Kamimura,

Uehara,

Yoneda

et al. 2023

Xenobiotica

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Quantitative Prediction of OATP-Mediated Disposition and Biliary Clearance Using Human Liver Chimeric Mice

Cited by 3 publications

References 56 publications

A Novel Approach to Predicting Organic Anion Transporting Polypeptide Function in Human Hepatic Drug Disposition and Biliary Clearance

A Novel Approach to Predicting Organic Anion Transporting Polypeptide Function in Human Hepatic Drug Disposition and Biliary Clearance

Quantitative prediction of CYP3A‐mediated drug–drug interactions by correctly estimating fraction metabolized using human liver chimeric mice

Empirical scaling factor for predicting human pharmacokinetic profiles of disproportionate metabolites using the Css–MRTpo method and chimeric mice with humanised livers

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