Extended Clearance Classification System (ECCS) informed approach for evaluating investigational drugs as substrates of drug transporters

Varma, MV; El-Kattan, AF; Feng, Bo; Steyn, SJ; Maurer, TS; Scott, Dennis O.; Rodrigues, A. David; Tremaine, LM

doi:10.1002/cpt.595

Cited by 38 publications

(45 citation statements)

References 3 publications

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“…In the same experimental conditions, permeability of ECCS class 1B drugs (high-permeability-highmolecular-weight acids/zwitterions) span a similar range, ∼5.5 (atorvastatin, pitavastatin) to 16 Â 10 26 cm/s (repaglinide) (Varma et al, 2015;El-Kattan et al, 2016). ECCS class 1B drugs are well proven to involve OATP-mediated hepatic uptake in their systemic clearance (Shitara et al, 2013;Varma et al, 2017a). Indeed, much evidence has been presented for "uptake-determined" clearance for highly permeable and metabolically labile drugs such as atorvastatin, bosentan, and glyburide (Zheng et al, 2009;Watanabe et al, 2010;Maeda et al, 2011;Yoshikado et al, 2017).…”

Section: Oat2-mediated Hepatic Uptake Clearancementioning

confidence: 98%

Organic Anion Transporter 2–Mediated Hepatic Uptake Contributes to the Clearance of High-Permeability–Low-Molecular-Weight Acid and Zwitterion Drugs: Evaluation Using 25 Drugs

Kimoto

Mathialagan

Tylaska

et al. 2018

J Pharmacol Exp Ther

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High-permeability-low-molecular-weight acids/zwitterions [i.e., extended clearance classification system class 1A (ECCS 1A) drugs] are considered to be cleared by metabolism with a minimal role of membrane transporters in their hepatic clearance. However, a marked disconnect in the in vitro-in vivo (IVIV) translation of hepatic clearance is often noted for these drugs. Metabolic rates measured using human liver microsomes and primary hepatocytes tend to underpredict. Here, we evaluated the role of organic anion transporter 2 (OAT2)-mediated hepatic uptake in the clearance of ECCS 1A drugs. For a set of 25 ECCS 1A drugs, in vitro transport activity was assessed using transporter-transfected cells and primary human hepatocytes. All but two drugs showed substrate affinity to OAT2, whereas four (bromfenac, entacapone, fluorescein, and nateglinide) also showed OATP1B1 activity in transfected cells. Most of these drugs (21 of 25) showed active uptake by plated human hepatocytes, with rifamycin SV (pan-transporter inhibitor) reducing the uptake by about 25%-95%. Metabolic turnover was estimated for 19 drugs after a few showed no measurable substrate depletion in liver microsomal incubations. IVIV extrapolation using in vitro data was evaluated to project human hepatic clearance of OAT2-alone substrates considering 1) uptake transport only, 2) metabolism only, and 3) transporter-enzyme interplay (extended clearance model). The transporter-enzyme interplay approach achieved improved prediction accuracy (average fold error = 1.9 and bias = 0.93) compared with the other two approaches. In conclusion, this study provides functional evidence for the role of OAT2-mediated hepatic uptake in determining the pharmacokinetics of several clinically important ECCS 1A drugs.

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Section: Oat2-mediated Hepatic Uptake Clearancementioning

confidence: 98%

Organic Anion Transporter 2–Mediated Hepatic Uptake Contributes to the Clearance of High-Permeability–Low-Molecular-Weight Acid and Zwitterion Drugs: Evaluation Using 25 Drugs

Kimoto

Mathialagan

Tylaska

et al. 2018

J Pharmacol Exp Ther

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“…The ECCS evaluates drugs based on a combination of permeability, ionization state, molecular weight, and the separation of metabolic and transport rate‐determining steps . According to the ECCS, drugs in the 1B and 3B classes should be the most promising markers of OATP1B activity, as these are compounds where hepatic uptake is the rate‐limiting step.…”

Section: Resultsmentioning

confidence: 99%

“…Solid horizontal line indicates median score for the class and dotted grey lines indicate the cutoff values for each index classification (poor < 4.4, good ≥ 7.6). ECCS determined by Varma et al . ECCS class 1A: high permeability, low molecular weight acids/zwitterions primarily cleared by metabolism; 1B: high permeability, high molecular weight acids/zwitterions primarily cleared by hepatic uptake; 2: high permeability bases/neutral compounds with high metabolic clearance; 3A: low permeability, low molecular weight acids/zwitterions with primarily renal clearance; 3B: low permeability, high molecular weight acids/zwitterions primarily cleared by hepatic uptake or renal elimination; 4: low permeability bases/neutral compounds primarily cleared through renal elimination.…”

Section: Resultsmentioning

confidence: 99%

“…Compounds with scores falling between 20% and 80% were classified as “moderate.” The maximum possible score, assuming the maximum of each category and all additional positive criteria, was 15.0 and the minimum was −5.5. To validate the proposed probe indexing system, index scores were evaluated against the corresponding extended clearance classification system (ECCS) class for those compounds, as the ECCS has been shown to accurately classify compounds based on sensitivity to hepatic uptake …”

Section: Methodsmentioning

confidence: 99%

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Identification and Evaluation of Clinical Substrates of Organic Anion Transporting Polypeptides 1B1 and 1B3

McFeely

Ritchie

et al. 2019

Clinical Translational Sci

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Organic anion transporting polypeptides (OATPs) 1B1 and 1B3 facilitate the uptake of drugs and endogenous compounds into the liver. In recent years, the impact of these transporters on drug–drug interactions (DDIs) has become a focus of research, and the evaluation of their role in drug disposition is recommended by regulatory agencies worldwide.1–3 Although sensitive substrates of OATP1B1/1B3 have been identified in the literature and probe drugs have been proposed by regulatory agencies, there is no general consensus on the ideal in vivo substrate for clinical DDI studies as analysis may be confounded by contribution from other metabolic and/or transport pathways.1–3 A thorough analysis of the available in vitro and in vivo data regarding OATP1B1/1B3 substrates was performed using the in vitro, clinical, and pharmacogenetic modules in the University of Washington Drug Interaction Database. A total of 34 compounds were identified and further investigated as possible clinical substrates using a novel indexing system. By analyzing the compounds for in vivo characteristics, including sensitivity to inhibition by known OATP1B1/1B3 inhibitors, selectivity for OATP1B1/1B3 compared with other transport and metabolic pathways, and safety profiles, a total of six compounds were identified as potential clinical markers of OATP1B1/1B3 activity.

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“…Although it cannot be entirely excluded that lipophilic compounds may penetrate the canalicular membrane of hepatocytes simply by passive diffusion, pharmacokinetic models describing hepatic clearance assume that only active transport of drugs or drug metabolites occurs across this membrane. Moreover, attempts are being made to classify drugs basedamong other factorson the role of transporters in their disposition, such as the biopharmaceutical drug disposition classification system (BDDCS), the extended clearance concept classification system (EC3S), or the extended clearance classification system (ECCS) [22][23][24][25][26]. These models, based on in vitro obtained data, predict the relative contributions of elimination pathways in the total clearance of a drug from the system.…”

Section: Introductionmentioning

confidence: 99%

Use of imaging to assess the activity of hepatic transporters

Hernández-Lozano

Langer

2020

Expert Opinion on Drug Metabolism & Toxicology

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Introduction: Membrane transporters of the SLC and ABC families are abundantly expressed in the liver, where they control the transfer of drugs/drug metabolites across the sinusoidal and canalicular hepatocyte membranes and play a pivotal role in hepatic drug clearance. Noninvasive imaging methods, such as PET, SPECT or MRI, allow for measuring the activity of hepatic transporters in vivo, provided that suitable transporter imaging probes are available. Areas covered: We give an overview of the working principles of imaging-based assessment of hepatic transporter activity. We discuss different currently available PET/SPECT radiotracers and MRI contrast agents and their applications to measure hepatic transporter activity in health and disease. We cover mathematical modeling approaches to obtain quantitative parameters of transporter activity and provide a critical assessment of methodological limitations and challenges associated with this approach. Expert opinion: PET in combination with pharmacokinetic modeling can be potentially applied in drug development to study the distribution of new drug candidates to the liver and their clearance mechanisms. This approach bears potential to mechanistically assess transporter-mediated drug-drug interactions, to assess the influence of disease on hepatic drug disposition and to validate and refine currently available in vitro-in vivo extrapolation methods to predict hepatic clearance of drugs. ARTICLE HISTORY

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Extended Clearance Classification System (ECCS) informed approach for evaluating investigational drugs as substrates of drug transporters

Cited by 38 publications

References 3 publications

Organic Anion Transporter 2–Mediated Hepatic Uptake Contributes to the Clearance of High-Permeability–Low-Molecular-Weight Acid and Zwitterion Drugs: Evaluation Using 25 Drugs

Organic Anion Transporter 2–Mediated Hepatic Uptake Contributes to the Clearance of High-Permeability–Low-Molecular-Weight Acid and Zwitterion Drugs: Evaluation Using 25 Drugs

Identification and Evaluation of Clinical Substrates of Organic Anion Transporting Polypeptides 1B1 and 1B3

Use of imaging to assess the activity of hepatic transporters

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