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Substrate-dependent Inhibition & Time-dependent Inhibition of OATP1B & its Impact on DDI Prediction
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Abstract:

1) Substrate-dependent and/or pre-incubation time dependent Ki values of OATP1Bs inhibitors; 

OATP1B is involved in the hepatic uptake of various anionic drugs, and drug-drug interactions (DDIs) can be caused by OATP1B inhibition. To address this issue, in vitro cell-based inhibition assay is routinely performed at nonclinical stages, and accurate determination of Ki values is critical to quantitatively assess the risk of DDIs. However, large interlaboratory variability was reported in the Ki values. The underlying mechanisms are not fully understood, but substrate- and time-dependent inhibition of OATP1B1 are considered to account at least in part for the variability.

Recent reports provided quantitative predictions for OATP1Bs-mediated DDIs between statins and cyclosporine A(CsA)/rifampicin (RIF) based on PBPK models. In the process of the analyses, the in vitro–in vivo discrepancies in the Ki values for OATPs were suggested. Such discrepancies may hamper the practical use of PBPK modeling for DDI prediction via a bottom-up approach, in which model parameters are determined by scaling up in vitro experimental results. To make a bottom-up predictions of OATP1Bs mediated DDI successful, substrate dependent and pre-incubation time dependent Ki values should be kept in mind.  Such a pre-incubation time dependent Ki values may be due to the trans-inhibition mechanism. 

In the process of the analyses, the in vitro–in vivo discrepancies in the Ki values for OATPs  and substrate dependent change of Ki values of  inhibitors were clarified. Such discrepancies and substrate dependency may hamper the practical use of PBPK modeling for DDI prediction by using endogenous biomarker. We therefore considered such substrate dependent change in Ki values between endogenous substrates and probe substrates obtained from in vitro experiment in the prediction of DDI as shown below.
 

2) Can Endogenous Biomarkers be Applied in Phase I Clinical Trials to Facilitate Subject Phenotyping and DDI Prediction?

 Earlier assessment of DDI risk in humans saves cost and time in conducting clinical DDI studies with minimal or negligible impact of DDI. Recent progress in the endogenous compounds that may be used as biomarkers for assessing DDI and genetic polymorphism based interindividual differences involving hepatic transporters in humans will be shown. Clinical investigations demonstrated that the AUC of endogenous substrates, such as coproporphyrins(CP), total and direct bilirubin, and some sulfate and glucuronide conjugates of bile acids, shows a significant correlation with an OATP1B substrate drugs such as statins, in terms of its inhibition by rifampicin(RIF), supporting the idea that endogenous substrates have adequate performance as probes for the quantitative analysis of transporter-mediated DDIs. We have started the construction of PBPK modeling of the endogenous substrates bilirubin, bilirubin glucuronide, CP-I, and glycochenodeoxycholate-3-sulfate. Such a PBPK model can reasonably account for these drugs’ interactions with rifampicin. PBPK modeling and simulation may help in the extrapolation of OATP1B-mediated change in plasma concentration of endogenous substrates to those of probe drug substrates.


References: 

Section 1:
1) Yoshikado T, Yoshida K, Kotani N, Nakada T, Asaumi R, Toshimoto K, Maeda K, Kusuhara H,Sugiyama Y. Quantitative Analyses of Hepatic OATP-Mediated Interactions Between Statins and Inhibitors Using PBPK Modeling With a Parameter Optimization Method. Clin Pharmacol Ther 100 (5):513-523 (2016) 
2) Kim SJ, Toshimoto K, Yao Y, Yoshikado T, Sugiyama Y. Quantitative Analysis of Complex Drug-Drug Interactions Between Repaglinide and Cyclosporin A/Gemfibrozil Using Physiologically Based Pharmacokinetic Models With In Vitro Transporter/Enzyme Inhibition Data. J Pharm Sci. 106(9):2715-2726 (2017).
3) Izumi S, Nozaki Y, Maeda K, Komori T, Takenaka O, Kusuhara H, Sugiyama Y. Investigation of the Impact of Substrate Selection on In Vitro Organic Anion Transporting Polypeptide 1B1 Inhibition Profiles for the Prediction of Drug-Drug Interactions. Drug Metab Dispos 43:235-247 (2015).
4) Shitara Y, Sugiyama Y. Preincubation-dependent and long-lasting inhibition of organic anion transporting polypeptide (OATP) and its impact on drug-drug interactions. Pharmacol Ther.177:67-80(2017).

Section 2:
5) Takehara I, Terashima H, Nakayama T, Yoshikado T, Yoshida M, Furihata K, Watanabe N, Maeda K, Ando O, Sugiyama Y, Kusuhara H. Investigation of Glycochenodeoxycholate Sulfate and Chenodeoxycholate Glucuronide as Surrogate Endogenous Probes for Drug Interaction Studies of OATP1B1 and OATP1B3 in Healthy Japanese Volunteers. Pharm Res. 34(8):1601-1614 (2017).
6) Rodrigues AD, Taskar KS, Kusuhara H, Sugiyama Y. Endogenous Probes for Drug Transporters: Balancing Vision with Reality. Clin Pharmacol Ther.106:2345-2356 (2018).
7) Yoshikado T, Toshimoto K, Maeda K, Kusuhara H, Kimoto E, Rodrigues AD, Chiba K, Sugiyama Y. PBPK Modeling of Coproporphyrin I as an Endogenous Biomarker for Drug Interactions Involving Inhibition of Hepatic OATP1B1 and OATP1B3. CPT Pharmacometrics Syst Pharmacol. 7:739-747 (2018).
8) Asaumi R, Menzel K, Lee W, Nunoya KI, Imawaka H, Kusuhara H, Sugiyama Y. Expanded Physiologically-Based Pharmacokinetic Model of Rifampicin for Predicting Interactions With Drugs and an Endogenous Biomarker via Complex Mechanisms Including Organic Anion Transporting Polypeptide 1B Induction. CPT Pharmacometrics Syst Pharmacol. 2019 Aug 16. doi: 10.1002/psp4.12457. [Epub ahead of print]

 

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