Fenamates and the potent inhibition of human liver phenol sulphotransferase.
1. The inhibition of the human liver phenol sulphotransferase (HL-PST) and catechol sulphotransferase (HL-CST) by five fenamates has been studied and the activities of HL-PST and HL-CST were measured with 4-nitrophenol and dopamine as substrates, respectively. 2. The IC50 for inhibition of HL-PST were 0.02 microM (mefenamic acid); 0.12 microM (tolfenamic acid); 0.28 microM (niflumic acid); 0.87 microM (meclofenamic acid) and 1.50 microM (flufenamic acid). 3. HL-CST was less susceptible than HL-PST to the inhibition by fenamates and the IC50 for HL-CST were 36 microM (tolfenamic acid); 70 microM (flufenamic acid); 76 microM (mefenamic acid); 180 microM (niflumic acid) and 185 microM (meclofenamic acid). 4. The ratios of the IC50 for HL-CST:HL-PST were drug-dependent and ranged from 47 (flufenamic acid) to 3800 (mefenamic acid). Mefenamic acid is a relatively potent and selective inhibitor of HL-PST. 5. The IC50 for HL-PST obtained with mefenamic acid was three orders of magnitude lower than the peak plasma concentration of this drug after an oral dose of 0.5 g. Accordingly, mefenamic acid should impair sulphation in vivo.
Vietri
M
M
Department of Neurosciences, Medical School, Pisa, Italy.
De Santi
C
C
Pietrabissa
A
A
Mosca
F
F
Pacifici
G M
GM
D015239:Arylsulfotransferase / Q000037:antagonists & inhibitors*; D004298:Dopamine / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005439:Flufenamic Acid / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008469:Meclofenamic Acid; D008528:Mefenamic Acid / Q000097:blood / Q000494:pharmacology; D015394:Molecular Structure; D009596:Nitrophenols / Q000378:metabolism; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D009596:Nitrophenols; D062367:ortho-Aminobenzoates; D008528:Mefenamic Acid; C009500:tolfenamic acid; D008469:Meclofenamic Acid; D005439:Flufenamic Acid; C001209:fenamic acid; D015239:Arylsulfotransferase; D004298:Dopamine; C024836:4-nitrophenol