Substrate recognition of renally eliminated angiotensin II receptor blockers by organic anion transporter 4

Drug Metab Pharmacokinet. 2021 Feb;36:100363. doi: 10.1016/j.dmpk.2020.10.002. Epub 2020 Oct 24.

Abstract

Organic anion transporter (OAT) 4, which is localized at the apical membrane of human renal proximal tubules, transports olmesartan, an angiotensin II receptor blocker (ARB). Many ARBs, including olmesartan, undergo partial tubular secretion as active forms, and inhibit OAT4-mediated uptake activity. Here, we examined the substrate recognition of various ARBs by OAT4 in order to assess whether OAT4 might be involved in the renal handling of ARBs. Concentration-dependent OAT4-mediated uptake of azilsartan, candesartan, carboxylosartan, losartan, and valsartan was observed with Km values of 6.6, 31, 7.2, 13, and 1.7 μM, respectively, in the absence of extracellular Cl-. In the presence of extracellular Cl-, OAT4-mediated uptake of dianionic ARBs (azilsartan, candesartan, carboxylosartan, and valsartan) was lower and reached a steady state faster than in the absence of extracellular Cl-. Thus, OAT4 is proposed to use extracellular Cl- as a counterpart for anion efflux. Our results suggest that OAT4 may play a role in the excretion of azilsartan, candesartan, carboxylosartan, and valsartan, as well as olmesartan. In contrast, OAT4-mediated uptake of losartan, a monoanionic ARB, was little affected by extracellular Cl-, suggesting that only OAT4-mediated dianion transport is Cl--sensitive.

Keywords: ARB; Angiotensin II receptor Blocker; OAT4; Organic anion transporter; Renal clearance.

MeSH terms

  • Angiotensin Receptor Antagonists / analysis
  • Angiotensin Receptor Antagonists / metabolism*
  • Angiotensin Receptor Antagonists / pharmacology
  • Chromatography, Liquid / methods
  • Dose-Response Relationship, Drug
  • HEK293 Cells
  • Humans
  • Kidney / drug effects
  • Kidney / metabolism*
  • Mass Spectrometry / methods
  • Organic Anion Transporters, Sodium-Independent / analysis
  • Organic Anion Transporters, Sodium-Independent / metabolism*
  • Substrate Specificity / physiology
  • Tandem Mass Spectrometry / methods*

Substances

  • Angiotensin Receptor Antagonists
  • Organic Anion Transporters, Sodium-Independent
  • SLC22A9 protein, human