Differential inhibition of hepatic and duodenal sulfation of (-)-salbutamol and minoxidil by mefenamic acid

Objective: The aim of this investigation was to determine whether mefenamic acid and salicylic acid inhibit the sulfation of (-)-salbutamol and minoxi dil in the human liver and duodenum, and if so, to ascertain whether the 50 % inhibitory concentration (IC50) estimates are different in the two tissue s. Methods: Sulfotransferase activities were measured for 10 mM (-)-salbutamol and 5 mM minoxidil, and the concentration of 3'-phosphoadenosine-5'-phosph osulphate-[S-35] was 0.4 mu M Results: The IC50 estimates for (-)-salbutamol and minoxidil sulfation of m efenamic acid were 72 +/- 5.4 nM and 1.5 +/- 0.6 mu M (liver), respectively , and 161 +/- 23 mu M and 420 +/- 18 mu M (duodenum), respectively. The fig ures for the liver were significantly lower (P < 0.0001) than those for the duodenum. The IC50 estimates for (-)-salbutamol sulfation of salicylic aci d were 93 +/- 11 mu M (liver) and 705 +/- 19 mu M (duodenum, P < 0.0001). S alicylic acid was a poor inhibitor of minoxidil sulfation. Conclusion: The IC50 estimates for (-)-salbutamol sulfation of mefenamic ac id and salicylic acid are lower than their unbound plasma concentrations af ter standard dosing, suggesting that mefenamic acid and salicylic acid shou ld inhibit the hepatic sulfation of (-)-salbutamol in vivo.