Renal Drug Transporters and Drug Interactions

Clin Pharmacokinet. 2017 Aug;56(8):825-892. doi: 10.1007/s40262-017-0506-8.

Abstract

Transporters in proximal renal tubules contribute to the disposition of numerous drugs. Furthermore, the molecular mechanisms of tubular secretion have been progressively elucidated during the past decades. Organic anions tend to be secreted by the transport proteins OAT1, OAT3 and OATP4C1 on the basolateral side of tubular cells, and multidrug resistance protein (MRP) 2, MRP4, OATP1A2 and breast cancer resistance protein (BCRP) on the apical side. Organic cations are secreted by organic cation transporter (OCT) 2 on the basolateral side, and multidrug and toxic compound extrusion (MATE) proteins MATE1, MATE2/2-K, P-glycoprotein, organic cation and carnitine transporter (OCTN) 1 and OCTN2 on the apical side. Significant drug-drug interactions (DDIs) may affect any of these transporters, altering the clearance and, consequently, the efficacy and/or toxicity of substrate drugs. Interactions at the level of basolateral transporters typically decrease the clearance of the victim drug, causing higher systemic exposure. Interactions at the apical level can also lower drug clearance, but may be associated with higher renal toxicity, due to intracellular accumulation. Whereas the importance of glomerular filtration in drug disposition is largely appreciated among clinicians, DDIs involving renal transporters are less well recognized. This review summarizes current knowledge on the roles, quantitative importance and clinical relevance of these transporters in drug therapy. It proposes an approach based on substrate-inhibitor associations for predicting potential tubular-based DDIs and preventing their adverse consequences. We provide a comprehensive list of known drug interactions with renally-expressed transporters. While many of these interactions have limited clinical consequences, some involving high-risk drugs (e.g. methotrexate) definitely deserve the attention of prescribers.

Publication types

  • Review

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / drug effects
  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / drug effects
  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / metabolism
  • Animals
  • Biological Transport / drug effects*
  • Biological Transport / physiology
  • Drug Interactions / physiology*
  • Female
  • Humans
  • Kidney / metabolism*
  • Kidney / ultrastructure
  • Kidney Tubules, Proximal / metabolism*
  • Male
  • Multidrug Resistance-Associated Proteins / drug effects
  • Multidrug Resistance-Associated Proteins / metabolism
  • Neoplasm Proteins / drug effects
  • Neoplasm Proteins / metabolism
  • Organic Anion Transporters / drug effects
  • Organic Anion Transporters / metabolism
  • Organic Anion Transporters, Sodium-Independent / drug effects
  • Organic Anion Transporters, Sodium-Independent / metabolism*
  • Organic Cation Transport Proteins / drug effects
  • Organic Cation Transport Proteins / metabolism*
  • Renal Agents / metabolism*
  • Renal Agents / pharmacokinetics
  • Renal Agents / therapeutic use

Substances

  • ABCC4 protein, human
  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • Multidrug Resistance-Associated Proteins
  • Neoplasm Proteins
  • Organic Anion Transporters
  • Organic Anion Transporters, Sodium-Independent
  • Organic Cation Transport Proteins
  • P-glycoprotein 2
  • Renal Agents
  • SLCO1A2 protein, human