Aldosterone glucuronidation by human liver and kidney microsomes and recombinant UDP-glucuronosyltransferases: inhibition by NSAIDs

Br J Clin Pharmacol. 2009 Sep;68(3):402-12. doi: 10.1111/j.1365-2125.2009.03469.x.


Aims: To characterize: i) the kinetics of aldosterone (ALDO) 18beta-glucuronidation using human liver and human kidney microsomes and identify the human UGT enzyme(s) responsible for ALDO 18beta-glucuronidation and ii) the inhibition of ALDO 18beta-glucuronidation by non-selective NSAIDs.

Methods: Using HPLC and LC-MS methods, ALDO 18beta-glucuronidation was characterized using human liver (n= 6), human kidney microsomes (n= 5) and recombinant human UGT 1A1, 1A3, 1A4, 1A5, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B10, 2B15, 2B17 and 2B28 as the enzyme sources. Inhibition of ALDO 18beta-glucuronidation was investigated using alclofenac, cicloprofen, diclofenac, diflunisal, fenoprofen, R- and S-ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, S-naproxen, pirprofen and tiaprofenic acid. A rank order of inhibition (IC(50)) was established and the mechanism of inhibition investigated using diclofenac, S-ibuprofen, indomethacin, mefenamic acid and S-naproxen.

Results: ALDO 18beta-glucuronidation by hepatic and renal microsomes exhibited Michaelis-Menten kinetics. Mean (+/-SD) K(m), V(max) and CL(int) values for HLM and HKCM were 509 +/- 137 and 367 +/- 170 microm, 1075 +/- 429 and 1110 +/- 522 pmol min(-1) mg(-1), and 2.36 +/- 1.12 and 3.91 +/- 2.35 microl min(-1) mg(-1), respectively. Of the UGT proteins, only UGT1A10 and UGT2B7 converted ALDO to its 18beta-glucuronide. All NSAIDs investigated inhibited ALDO 18beta-G formation by HLM, HKCM and UGT2B7. The rank order of inhibition (IC(50)) of renal and hepatic ALDO 18beta-glucuronidation followed the general trend: fenamates > diclofenac > arylpropionates.

Conclusion: A NSAID-ALDO interaction in vivo may result in elevated intra-renal concentrations of ALDO that may contribute to the adverse renal effects of NSAIDs and their effects on antihypertensive drug response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aldosterone / metabolism*
  • Anti-Inflammatory Agents, Non-Steroidal / metabolism
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Chromatography, High Pressure Liquid
  • Female
  • Glucuronides / metabolism*
  • Glucuronosyltransferase / antagonists & inhibitors
  • Glucuronosyltransferase / metabolism*
  • Humans
  • Inhibitory Concentration 50
  • Kidney / metabolism
  • Kinetics
  • Liver / metabolism
  • Male
  • Microsomes / enzymology
  • Microsomes / metabolism*
  • Middle Aged


  • Anti-Inflammatory Agents, Non-Steroidal
  • Glucuronides
  • Aldosterone
  • Glucuronosyltransferase