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Plasma Protein Binding Refinement of the Extended Clearance Classification System: Subclasses for Predicting Hepatic Uptake or Renal Clearance for Classes 1B and 3B

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Abstract

Background and Objectives

The Extended Clearance Classification System (ECCS) was established to facilitate the timely anticipation of clearance rate determination according to the physicochemical characteristics of a given compound and in vitro passive membrane permeability. Unfortunately, distinguishing between renal and hepatic uptake clearance mechanisms using ECCS class 3B is not possible. We determined the effects of plasma protein binding (PPB) on major hepatic organic anion transporting polypeptide (OATP) and renal organic anion transporter (OAT) substrates. A modified ECCS could predict when renal or hepatic uptake mechanisms were the main clearance rate determinants (accounting for ≥ 70% of total clearance).

Methods

A dataset of 66 human OATP and 41 OAT substrates was analyzed to determine the effect of PPB. A total of 63 acidic and zwitterionic, and high-molecular-weight (MW > 400 Da) compounds, including 50 drugs in ECCS classes 1B and 3B, were reanalyzed considering their PPB.

Results

Statistical analyses revealed that hepatic uptake transporter (OATP1B1 and OATP1B3) substrates possess a high PPB rate of ≥ 90%, whereas OAT1 and/or OAT3 substrates possess low PPB rates of < 90%. By analyzing the 63 drugs on the basis of their PPB, the active hepatic uptakes of acids and zwitterions were determined to be the main clearance mechanisms, with PPB ≥ 90%, whereas renally eliminated drugs exhibited limited PPB (< 90%).

Conclusions

Therefore, PPB is an effective parameter for defining clearance rate determination for acidic and zwitterionic drugs with high MWs. Using PPB as an additional parameter in ECCS, clearance mechanisms for class 1B and 3B compounds can be predicted, and OATP and OAT substrates may be readily distinguished.

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Acknowledgements

We would like to thank Editage (www.editage.com) for English language editing.

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Author notes

  1. Yahya Khawaja and Fatma Haddad contributed equally to this work.

Authors and Affiliations

  1. Faculty of Pharmacy, Al-Quds University, Abu Deis, Palestine

    Yahya Khawaja & Fatma Haddad

  2. Faculty of Life Sciences, University of Bradford, Bradford, BD7 1DP, UK

    Fatma Haddad

  3. Faculty of Medicine, Al-Quds University, P.O. Box 20002, Abu Deis, 9119401, Palestine

    Hussein Hallak

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  1. Yahya Khawaja
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Correspondence to Hussein Hallak.

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Y.K. and F.H. made substantial contributions to the conception of the work as well as analysis and interpretation of data, drafted the work, and revised it critically for important intellectual content. H.H. supervised the work, approved the version to be published, and agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Yahya Khawaja, Fatma Haddad, and Hussein Hallak declare that they have no conflicts of interest.

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Khawaja, Y., Haddad, F. & Hallak, H. Plasma Protein Binding Refinement of the Extended Clearance Classification System: Subclasses for Predicting Hepatic Uptake or Renal Clearance for Classes 1B and 3B. Eur J Drug Metab Pharmacokinet 48, 63–73 (2023). https://doi.org/10.1007/s13318-022-00806-4

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