The extended clearance model and its use for the interpretation of hepatobiliary elimination data

Camenisch, Gian; Riede, Julia; Kunze, Annett; Huwyler, Jörg; Poller, Birk; Umehara, Kenichi

doi:10.5599/admet.3.1.144

Cited by 25 publications

(20 citation statements)

References 12 publications

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“…Recently, Camenisch and coworkers [34–36] have proposed an Extended Clearance Concept Classification System (ECCCS) to identify the rate-determinant hepatic clearance step for an NME and then provide a quantitative prediction of in vivo hepatic clearance. Varma et al [19] also proposed an Extended Clearance Classification System (ECCS) to predict clearance mechanisms early in drug discovery.…”

Section: Use Of Bddcs To Predict Nme Drug Disposition Characteristicsmentioning

confidence: 99%

BDDCS, the Rule of 5 and drugability

Benet

Hosey-Cojocari

Ursu

et al. 2016

Advanced Drug Delivery Reviews

559

305

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The rule of 5 methodology appears to be as useful today in defining drugability as when it was proposed, but recognizing that the database that we used includes only drugs that successfully reached the market. We do not view additional criteria necessary nor did we find significant deficiencies in the four Rule of 5 criteria originally proposed by Lipinski and coworkers. BDDCS builds upon the Rule of 5 and can quite successfully predict drug disposition characteristics for drugs both meeting and not meeting Rule of 5 criteria. More recent expansions of classification systems have been proposed and do provide useful qualitative and quantitative predictions for clearance relationships. However, the broad range of applicability of BDDCS beyond just clearance predictions gives a great deal of further usefulness for the combined Rule of 5/BDDCS system.

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Section: Use Of Bddcs To Predict Nme Drug Disposition Characteristicsmentioning

confidence: 99%

BDDCS, the Rule of 5 and drugability

Benet

Hosey-Cojocari

Ursu

et al. 2016

Advanced Drug Delivery Reviews

559

305

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“…The inability to precisely quantify and/or predict clearance as well as the concentrations of a drug in the tissue targeted for treatment can have major implications for drug safety and efficacy. Several drug clearance classification systems based on in vitro obtained properties of the drugs under development have been proposed to predict the major clearance route of new molecular entities [21][22][23][24]153]. Since the liver is the major organ involved in the excretion of drugs from the organism, determination of the total hepatic clearance is a pivotal step in understanding and predicting the total systemic clearance of a drug.…”

Section: Expert Opinionmentioning

confidence: 99%

“…Based on the recognition that hepatic transporters play a pivotal role in hepatic drug clearance, efforts have been made to incorporate the action of transporters into pharmacokinetic models describing the hepatic clearance of drugs, such as the extended clearance model (ECM) [20]. The ECM provides the mathematical background to identify the ratedetermining hepatic clearance step of a drug assuming that the total hepatic intrinsic drug clearance can be expressed as a combination of the individual hepatic elimination processes: passive diffusion and active transport across the sinusoidal membrane into the hepatocytes, potential metabolism of the drug in the cytosol, passive or active backflux into the systemic circulation and efflux clearance at the canalicular membrane of hepatocytes [6,21]. 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.…”

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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“…Alternatively, Kp uu can be calculated from individual in vitro hepatic process clearances (i.e., active and passive hepatic uptake and efflux, metabolism, biliary secretion) according to the extended clearance model (ECM) ( Table 1). 8,[14][15][16][17][18][19] Our group recently determined ECM-derived Kp uu data and corresponding intrahepatic concentrations for a set of compounds to predict drug-induced cholestasis from bile salt export pump inhibition data. 19 The approach provided superior predictions as compared to using unbound systemic concentrations, thus demonstrating the utility of the ECM-derived Kp uu method.…”

Section: Introductionmentioning

confidence: 99%

“…Four ECM classes have been derived based on the processes that govern hepatic drug clearance and disposition (i.e., Kp uu ). 14,15,19 ECM class 1 and class 2 compounds enter the liver only via passive diffusion, whereas class 3 and class 4 compounds require additional transporter-mediated hepatic uptake. The intrinsic clearance of ECM class 1 and 3 compounds is higher than passive sinusoidal permeability.…”

Section: Introductionmentioning

confidence: 99%

Current In Vitro Methods to Determine Hepatic Kp uu : A Comparison of Their Usefulness and Limitations

Riede

Camenisch

Huwyler

et al. 2017

Journal of Pharmaceutical Sciences

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Unbound intrahepatic drug concentrations determine the interaction potential with intracellular targets related to toxicity, pharmacokinetics, or pharmacodynamics. Recently, the unbound liver-to-blood partition coefficient (Kp) based on the Extended Clearance Model (ECM) has been developed providing indirect estimates of unbound intrahepatic drug concentrations. This study aimed to determine Kp for 18 diverse drug compounds by 3 alternative in vitro methods and to compare the outcome with the ECM approach. Kp was calculated from independent measurements of hepatocellular drug accumulation (Kp) and unbound fraction in hepatocytes (fu) either assessed from steady-state accumulation at 4°C (temperature method), using equilibrium dialysis (homogenization method), or empirically from logD (logD method). Deviations to ECM-based Kp data were closely linked to the absence of intrinsic clearance processes (metabolism, biliary secretion) in the investigated methods. Differences in fu additionally contributed to deviations in Kp. The homogenization method generally provided lowest fu values, especially for compounds with high molecular weight or low logD. Kp values of compounds with low intrinsic clearance correlated well between the ECM and temperature methods independent of physicochemical properties. Therefore, only the ECM provides an integrated quantitative determination of hepatic Kp. Temperature and homogenization methods, however, represent useful alternatives if compound properties are appropriately considered.

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The extended clearance model and its use for the interpretation of hepatobiliary elimination data

Abstract: Hepatic elimination is a function of the interplay between different processes

Cited by 25 publications

References 12 publications

BDDCS, the Rule of 5 and drugability

BDDCS, the Rule of 5 and drugability

Use of imaging to assess the activity of hepatic transporters

Current In Vitro Methods to Determine Hepatic Kp uu : A Comparison of Their Usefulness and Limitations

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