Overview of Transporters in Pharmacokinetics and Drug Discovery

Abstract

Transporters play important roles in absorption, distribution, metabolism, and elimination (ADME) processes, as well as drug pharmacokinetics (PK) and pharmacodynamics (PD). They are also important in maintaining the homeostasis of endogenous compounds and nutrients in the body. Increasing evidences also suggest that they are important in mediating drug-drug interactions (DDIs). While the significance of transporters in drug pharmacodynamics and DDIs are beyond the scope of this overview, the basic concepts of transporters, their contributions in membrane permeation processes, and their roles in influencing drug ADME pathway and PK will be discussed. © 2018 by John Wiley & Sons, Inc.

RCSB Protein Data Bank: Enabling biomedical research and drug discovery

“…Membrane transporters play central roles in ADME (absorption, distribution, metabolism, elimination) and pharmacodynamic properties of drugs. 75 The human genome encodes >400 membrane transporters that fall into two superfamilies:…”

“…For example, P-gp and BCRP (Breast Cancer Resistance Protein), found on the luminal surfaces of cells in the gut, modulate oral bioavailability of drug, and are, therefore, key determinants of ADME properties. 75,82 For example, increased expression of P-gp in cancer cells confers resistance to various chemotherapeutic agents. 3DEM structures, beginning with the complex of P-gp with cyclic peptide inhibitors (PDB 3g61), 83 are revealing the mechanism(s) of action of these transporters and modes of targeted inhibition.…”

“…Membrane transporters play central roles in ADME (absorption, distribution, metabolism, and elimination) and pharmacodynamic properties of drugs. 75 The human genome encodes >400 membrane transporters that fall into two superfamilies: ATP-binding cassette (ABC) superfamily and solute carrier (SLC) family. All ABC transporters and many SLC transporters function as active transporters, using either ATP or electrochemical gradients to drive transport.…”

“…Sequence mapping of PDB structures to the Transporter Classification Database (http://www.tcdb.org) identified 9,834 transporter structures in the PDB archive (as of July 2019, Table ). Membrane transporters play central roles in ADME (absorption, distribution, metabolism, and elimination) and pharmacodynamic properties of drugs . The human genome encodes >400 membrane transporters that fall into two superfamilies: ATP‐binding cassette (ABC) superfamily and solute carrier (SLC) family.…”

“…ABC transporters are also relevant to human health and therapies. For example, P‐gp and breast cancer resistance protein, found on the luminal surfaces of cells in the gut, modulate oral bioavailability of drug, and are, therefore, key determinants of ADME properties . For example, increased expression of P‐gp in cancer cells confers resistance to various chemotherapeutic agents.…”