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

摘要: WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Carboxylic acid NSAIDs are extensively glucuronidated as either the parent drug or hydroxylated metabolites and UGT2B7 is ranked highest in terms of NSAID-glucuronidation activity. • NSAIDs cause adverse renal effects including sodium water retention hyperkalaemia. • In human kidney mineralocorticoid aldosterone directly to form 18β-glucuronide. WHAT STUDY ADDS • Human liver microsomes UGT1A10 catalyze aldosterone18β-glucuronidation. • Non-selective inhibit hepatic aldosterone18β-glucuronidation vivo this may lead elevated intra-renal concentrations hormone. • Common involvement NSAID glucuronidation predicates an NSAID-aldosterone interaction that explain part clinical observations variable on electrolytes, fluid blood pressure. AIMS To characterize: i) kinetics (ALDO) 18β-glucuronidation using identify UGT enzyme(s) responsible for ALDO ii) inhibition by non-selective NSAIDs. METHODS Using HPLC LC-MS methods, was characterized (n= 6), 5) recombinant 1A1, 1A3, 1A4, 1A5, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B10, 2B15, 2B17 2B28 enzyme sources. Inhibition investigated alclofenac, cicloprofen, diclofenac, diflunisal, fenoprofen, R- S-ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic S-naproxen, pirprofen tiaprofenic acid. A rank order (IC50) established mechanism S-naproxen. RESULTS ALDO exhibited Michaelis-Menten kinetics. Mean (±SD) Km, Vmax CLint values HLM HKCM were 509 ± 137 367 170 µm, 1075 429 1110 522 pmol min−1 mg−1, 2.36 1.12 3.91 2.35 µl min−1 mg−1, respectively. Of proteins, only converted its 18β-glucuronide. All inhibited 18β-G formation HLM, UGT2B7. The followed general trend: fenamates > diclofenac arylpropionates. CONCLUSION A NSAID-ALDO result contribute their antihypertensive response.