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 minoxidil in the human liver and duodenum, and if so, to ascertain whether the 50% inhibitory concentration (IC50) estimates are different in the two tissues.


METHODS
Sulfotransferase activities were measured for 10 mM (-)-salbutamol and 5 mM minoxidil, and the concentration of 3'-phosphoadenosine-5'-phosphosulphate-[35S] was 0.4 microM.


RESULTS
The IC50 estimates for (-)-salbutamol and minoxidil sulfation of mefenamic acid were 72 +/- 5.4 nM and 1.5 +/- 0.6 microM (liver), respectively, and 161 + 23 microM and 420 +/- 18 microM (duodenum), respectively. The figures for the liver were significantly lower (P < 0.0001) than those for the duodenum. The IC50 estimates for (-)-salbutamol sulfation of salicylic acid were 93 +/- 11 microM (liver) and 705 +/- 19 microM (duodenum, P < 0.0001). Salicylic acid was a poor inhibitor of minoxidil sulfation.


CONCLUSIONS
The IC50 estimates for (-)-salbutamol sulfation of mefenamic acid and salicylic acid are lower than their unbound plasma concentrations after standard dosing, suggesting that mefenamic acid and salicylic acid should inhibit the hepatic sulfation of (-)-salbutamol in vivo.
Vietri
M
M
Department of Neurosciences, Medical School, Pisa, Italy.
Pietrabissa
A
A
Spisni
R
R
Mosca
F
F
Pacifici
G M
GM
D000318:Adrenergic beta-Agonists / Q000493:pharmacokinetics*; D000368:Aged; D000420:Albuterol / Q000493:pharmacokinetics*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000493:pharmacokinetics*; D004298:Dopamine / Q000378:metabolism; D004347:Drug Interactions; D004386:Duodenum / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008528:Mefenamic Acid / Q000494:pharmacology*; D008875:Middle Aged; D008914:Minoxidil / Q000493:pharmacokinetics*; D009596:Nitrophenols / Q000378:metabolism; D013431:Sulfates / Q000097:blood
D000318:Adrenergic beta-Agonists; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000959:Antihypertensive Agents; D009596:Nitrophenols; D013431:Sulfates; D008528:Mefenamic Acid; D008914:Minoxidil; D000420:Albuterol; D004298:Dopamine; C024836:4-nitrophenol