Transporter–enzyme interplay and the hepatic drug clearance: what have we learned so far?

Alluri, Ravindra Varma; Li, Rui; Varma, Manthena V.

doi:10.1080/17425255.2020.1749595

Cited by 16 publications

(12 citation statements)

References 164 publications

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“…However, oral exposure of atorvastatin, pravastatin, and rosuvastatin were shown to be elevated by inhibitors, such as itraconazole and fenebrutinib, which can be explained by the effects on other disposition mechanisms (e.g., CYP3A metabolism or intestinal/ biliary efflux inhibition). 4,31 OATP1B1 Rvalues were plotted against AUC ratios of CP-I and statins (a total of 85 substrate-inhibitor pairs) in order to define cutoff criteria utilizing the current dataset (Figure 1B). A reliable cutoff for Rvalue could not be defined based on atorvastatin, pravastatin, and rosuvastatin DDI data, likely due to nonspecific effects of inhibitors (e.g., inhibition of CYP3A, MRP2, and breast cancer resistance protein (BCRP)).…”

Section: Resultsmentioning

confidence: 99%

“…The PKs of statins, such as atorvastatin, pravastatin, and rosuvastatin, is not only determined by OATP1B-mediated hepatic uptake, but also involve other disposition mechanisms like CYP3A-mediated metabolism (atorvastatin), MRP2-or BCRPmediated intestinal or biliary efflux (pravastatin and rosuvastatin). 31,33 Additionally, many inhibitor drugs modulate multiple mechanisms along the gut and liver axis. Therefore, defining Rvalue cutoff criterion based on simple static analysis while assuming OATP1B inhibition alone is somewhat unrealistic.…”

Section: Discussionmentioning

confidence: 99%

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Biomarker‐Informed Model‐Based Risk Assessment of Organic Anion Transporting Polypeptide 1B Mediated Drug‐Drug Interactions

Kimoto

Costales

West

et al. 2021

Clin Pharma and Therapeutics

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Quantitative prediction of drug‐drug interactions (DDIs) involving organic anion transporting polypeptide (OATP)1B1/1B3 inhibition is limited by uncertainty in the translatability of experimentally determined in vitro inhibition potency (half‐maximal inhibitory concentration (IC50)). This study used an OATP1B endogenous biomarker‐informed physiologically‐based pharmacokinetic (PBPK) modeling approach to predict the effect of inhibitor drugs on the pharmacokinetics (PKs) of OATP1B substrates. Initial static analysis with about 42 inhibitor drugs, using in vitro IC50 values and unbound liver inlet concentrations (Iin,max,u), suggested in vivo OATP1B inhibition risk for drugs with R‐value (1+ Iin,max,u/IC50) above 1.5. A full‐PBPK model accounting for transporter‐mediated hepatic disposition was developed for coproporphyrin I (CP‐I), an endogenous OATP1B biomarker. For several inhibitors (cyclosporine, diltiazem, fenebrutinib, GDC‐0810, itraconazole, probenecid, and rifampicin at 3 different doses), PBPK models were developed and verified against available CP‐I plasma exposure data to obtain in vivo OATP1B inhibition potency—which tend to be lower than the experimentally measured in vitro IC50 by about 2‐fold (probenecid and rifampicin) to 37‐fold (GDC‐0810). Models verified with CP‐I data are subsequently used to predict DDIs with OATP1B probe drugs, rosuvastatin and pitavastatin. The predicted and observed area under the plasma concentration‐time curve ratios are within 20% error in 55% cases, and within 30% error in 89% cases. Collectively, this comprehensive study illustrates the adequacy and utility of endogenous biomarker‐informed PBPK modeling in mechanistic understanding and quantitative predictions of OATP1B‐mediated DDIs in drug development.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Biomarker‐Informed Model‐Based Risk Assessment of Organic Anion Transporting Polypeptide 1B Mediated Drug‐Drug Interactions

Kimoto

Costales

West

et al. 2021

Clin Pharma and Therapeutics

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“…Preclinical and clinical data support the significance of organic anion-transporting polypeptide (OATP) 1B1 and OATP1B3 in the hepatic uptake of several highmolecular mass (MM) acidic/zwitterionic drugs (e.g., statins, sartans, and certain glinides). In addition to active uptake, hepatic metabolism and/or biliary efflux may also contribute to the human hepatic clearance of acidic/zwitterionic compounds (Alluri et al, 2020;Steyn and Varma, 2020). According to the extended clearance classification system (ECCS) framework, hepatic clearance of high MM (.400 Da) acids/zwitterions involves OATP1B1/1B3-mediated uptake irrespective of their passive membrane permeability (Varma et al, 2015;El-Kattan and Varma, 2018).…”

Section: Introductionmentioning

confidence: 99%

Organic Anion–Transporting Polypeptide 1B1/1B3–Mediated Hepatic Uptake Determines the Pharmacokinetics of Large Lipophilic Acids: In Vitro–In Vivo Evaluation in Cynomolgus Monkey

Eng

West

et al. 2021

J Pharmacol Exp Ther

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It is generally presumed that uptake transport mechanisms are of limited significance in hepatic clearance for lipophilic or high passive-permeability drugs. In this study, we evaluated the mechanistic role of the hepato-selective organic aniontransporting polypeptides (OATPs) 1B1/1B3 in the pharmacokinetics of compounds representing large lipophilic acid space. Intravenous pharmacokinetics of 16 compounds with molecular mass ∼400-730 Da, logP ∼3.5-8, and acid pKa ,6 were obtained in cynomolgus monkey after dosing without and with a single-dose rifampicin-OATP1B1/1B3 probe inhibitor. Rifampicin (30 mg/kg oral) significantly (P , 0.05) reduced monkey clearance and/or steady-state volume of distribution (VDss) for 15 of 16 acids evaluated. Additionally, clearance of danoprevir was reduced by about 35%, although statistical significance was not reached. A significant linear relationship was noted between the clearance ratio (i.e., ratio of control to treatment groups) and VDss ratio, suggesting hepatic uptake contributes to the systemic clearance and distribution simultaneously. In vitro transport studies using primary monkey and human hepatocytes showed uptake inhibition by rifampicin (100 mM) for compounds with logP #6.5 but not for the very lipophilic acids (logP . 6.5), which generally showed high nonspecific binding in hepatocyte incubations. In vitro uptake clearance and fraction transported by OATP1B1/1B3 (f t,OATP1B ) were found to be similar in monkey and human hepatocytes. Finally, for compounds with logP #6.5, good agreement was noted between in vitro f t,OATP1B and clearance ratio (as well as VDss ratio) in cynomolgus monkey. In conclusion, this study provides mechanistic evidence for the pivotal role of OATP1B-mediated hepatic uptake in the pharmacokinetics across a wide, large lipophilic acid space. SIGNIFICANCE STATEMENTThis study provides mechanistic insight into the pharmacokinetics of a broad range of large lipophilic acids. Organic anion-transporting polypeptides 1B1/1B3-mediated hepatic uptake is of key importance in the pharmacokinetics and drug-drug interactions of almost all drugs and new molecular entities in this space. Diligent in vitro and in vivo transport characterization is needed to avoid the false negatives often noted because of general limitations in the in vitro assays while handling compounds with such physicochemical attributes.

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“…Extended clearance classification system (ECCS) 1B/3B compounds) (Varma et al, 2015;Varma et al, 2017a). However, once cleared from the blood compartment to liver, high permeable OATP substrates (class 1B) are metabolized and excreted from the body as phase I and/or phase II metabolites, while low permeable (class 3B) OATP substrates are predominantly eliminated unchanged in the bile (Kimoto et al, 2017;Varma et al, 2017c;Alluri et al, 2020). Although considerable progress has been made in the mechanistic characterization of the various disposition pathways, accurate prediction of hepatic clearance via transporters from in vitro tools is still challenging (Jones et al, 2012;Menochet et al, 2012;Zamek-Gliszczynski et al, 2013;Li et al, 2014a).…”

Section: Introductionmentioning

confidence: 99%

Effect of Human Plasma on Hepatic Uptake of Organic Anion–Transporting Polypeptide 1B Substrates: Studies Using Transfected Cells and Primary Human Hepatocytes

Ryu

Tess

et al. 2020

Drug Metab Dispos

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ABBREVIATIONS: AMUF, albumin-mediated uptake factor; PS inf,u , apparent unbound uptake clearance; CL int,h , intrinsic hepatic clearance; CL h , plasma hepatic clearance; C/M ratio, cell-tounbound media ratio; ECCS, extended clearance classification system; ESF, empirical scaling factor; f u,p , fraction unbound in plasma; IVIVE, in vitro-in vivo extrapolation; K d,m , dissociation constant of the bound albumin from the cell surface; OATP, organic anion-transporting polypeptide; Q h , hepatic blood flow; R bp , blood-to-plasma ratio This article has not been copyedited and formatted. The final version may differ from this version.

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Transporter–enzyme interplay and the hepatic drug clearance: what have we learned so far?

Cited by 16 publications

References 164 publications

Biomarker‐Informed Model‐Based Risk Assessment of Organic Anion Transporting Polypeptide 1B Mediated Drug‐Drug Interactions

Biomarker‐Informed Model‐Based Risk Assessment of Organic Anion Transporting Polypeptide 1B Mediated Drug‐Drug Interactions

Organic Anion–Transporting Polypeptide 1B1/1B3–Mediated Hepatic Uptake Determines the Pharmacokinetics of Large Lipophilic Acids: In Vitro–In Vivo Evaluation in Cynomolgus Monkey

Effect of Human Plasma on Hepatic Uptake of Organic Anion–Transporting Polypeptide 1B Substrates: Studies Using Transfected Cells and Primary Human Hepatocytes

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