Plasma Protein Binding Refnement of the Extended Clearance Classifcation System: Subclasses for Predicting Hepatic Uptake or Renal Clearance for Classes 1B and 3B
Date
2022-11-28
Authors
Yahya Khawaja
Fatma Haddad
Hussein Hallak
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Abstract
Background and Objectives: The Extended Clearance Classifcation 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 efects of plasma protein binding (PPB) on major hepatic organic anion transporting polypeptide (OATP) and renal organic anion transporter (OAT) substrates. A modifed 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 efect 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 mecha-nisms, with PPB ≥90%, whereas renally eliminated drugs exhibited limited PPB (<90%).
Conclusions: Therefore, PPB is an efective parameter for defning 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.