Role of membrane transporters in the safety profile of drugs.
It has increasingly been recognized that few molecules move across the cell membrane without the assistance of transporter proteins. Large superfamilies of transporter proteins have been identified in every living cell, including microorganisms and mitochondria. This report reviews the role of transporters in physiology and pharmacology, and identifies where this may have an impact on drug efficacy and toxicity. This new understanding will require a fresh appreciation of pharmacokinetics and drug effects, as the current paradigms are based largely on the assumption that drug molecules have a reasonable unrestricted permeability across membranes. Rather than just focusing on clearance changes and central compartment pharmacokinetics, it will become increasingly necessary to examine the peripheral tissue distribution of drugs to more accurately predict drug efficacy and toxicity.
Lee
Edmund Jon Deoon
EJ
National University of Singapore, Clinical Research Centre, Department of Pharmacology, Singapore. edlee@nus.edu.sg
Lean
Choo Bee
CB
Limenta
Lie Michael George
LM
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000042:Absorption; D026905:Amino Acid Transport Systems / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D064420:Drug-Related Side Effects and Adverse Reactions; D018565:Food-Drug Interactions; D006801:Humans; D026901:Membrane Transport Proteins / Q000502:physiology*; D004364:Pharmaceutical Preparations / Q000378:metabolism / Q000652:urine; D010599:Pharmacokinetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013347:Subcellular Fractions / Q000378:metabolism; D014018:Tissue Distribution
D018528:ATP-Binding Cassette Transporters; D026905:Amino Acid Transport Systems; D026901:Membrane Transport Proteins; D004364:Pharmaceutical Preparations; D012333:RNA, Messenger