Navigating Transporter Sciences in Pharmacokinetics Characterization Using the Extended Clearance Classification System

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Ayman F El-Kattan, Manthena V S Varma

Abstract

Membrane transporters play an important role in the absorption, distribution, clearance, and elimination of drugs. Supported by the pharmacokinetics data in human, several transporters including organic anion transporting polypeptide (OATP)1B1, OATP1B3, organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)2, multidrug and toxin extrusion (MATE) proteins, P-glycoprotein and breast cancer resistance protein are suggested to be of clinical relevance. An early understanding of the transporter role in drug disposition and clearance allows reliable prediction/evaluation of pharmacokinetics and changes due to drug-drug interactions (DDIs) or genetic polymorphisms. We recently proposed an extended clearance classification system (ECCS) based on simple drug properties (i.e., ionization, permeability, and molecular weight) to predict the predominant clearance mechanism. According to this framework, systemic clearance of class 1B and 3B drugs is likely determined by the OATP-mediated hepatic uptake. Class 3A and 4 drugs, and certain class 3B drugs, are predominantly cleared by renal, wherein, OAT1, OAT3, OCT2, and MATE proteins could contribute to their active renal secretion. Intestinal efflux and uptake transporters l...Continue Reading

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Citations

Feb 1, 2019·European Journal of Drug Metabolism and Pharmacokinetics·Jennypher MudunuruManoj Maniar
Feb 2, 2019·Clinical and Translational Science·Savannah J McFeelyIsabelle Ragueneau-Majlessi
Jun 9, 2018·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Rachel E KosaManthena V Varma
Apr 13, 2019·The Journal of Pharmacology and Experimental Therapeutics·Yi-An BiA David Rodrigues
Apr 11, 2018·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Qingcheng MaoJoanne Wang
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Jan 18, 2020·Expert Opinion on Drug Metabolism & Toxicology·Irene Hernández Lozano, Oliver Langer
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Sep 29, 2020·Journal of Medicinal Chemistry·David A TessManthena V S Varma
Nov 15, 2021·Drug Discovery Today·Kit-Kay MakMallikarjuna Rao Pichika

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