The kidney--the body's playground for drugs: an overview of renal drug handling with selected clinical correlates.
A greater understanding of transport mechanisms contributing to renal drug handling may be useful in predicting drug clearance and drug interactions. Renal clearance is a dynamic process expressed as the sum of the rates of glomerular filtration and tubular secretion minus the rate of tubular reabsorption. Because the transport of drugs is often against a concentration gradient, renal secretion is mostly an active process involving a variety of transporter mechanisms. Discoveries from molecular biology techniques and gene 'knock-out' experiments have identified a variety of renal tubular proteins responsible for the transport of organic cations, organic anions, neutral and cationic hydrophobic compounds, anionic conjugates and specific agents such as prostaglandins. The discovery of a P-glycoprotein (P-gp) transporter at the apical membrane of renal tubular cells is particularly important. By elucidating compounds that act as substrates, inhibitors or inducers of transport proteins, pharmacologists and clinicians may better understand renal drug clearance. This paper provides a brief overview of several identified renal transport proteins including organic anion transporters, organic cation transporters, ATP-dependent transporters (multidrug resistance [P-gp] and multi-drug resistance associated protein), nucleoside transporters (sodium-dependent purine nucleoside transporter and concentrative nucleoside transporter 1) and peptide transporters. A special focus on known P-gp-mediated drug interactions is included to demonstrate the clinical relevance of transporter protein science. At the patient level, this may lead to novel approaches to alter in vivo pharmacokinetics and improve drug safety through a greater understanding of toxic substrate clearance and drug interactions.
Perri
Dan
D
Department of Medicine, McMaster University, Hamilton, Canada. dan.perri@utoronto.ca
Ito
Shinya
S
Rowsell
Victoria
V
Shear
Neil H
NH
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D027682:Cation Transport Proteins / Q000378:metabolism; D015658:HIV Infections / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000033:anatomy & histology / Q000378:metabolism / Q000502:physiology*; D007684:Kidney Tubules / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D033703:Nucleoside Transport Proteins / Q000378:metabolism; D027361:Organic Anion Transporters / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010599:Pharmacokinetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D027682:Cation Transport Proteins; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D033703:Nucleoside Transport Proteins; D027361:Organic Anion Transporters; D004364:Pharmaceutical Preparations; C043912:peptide permease