Properties of the reversible, K(+)-competitive inhibitor of the gastric (H+/K+)-ATPase, SK&F 97574. II. Pharmacological properties.
SK&F 97574 [3-Butryl-4-(2-methylamino)-8-(2-hydroxyethoxy) quinoline] is a potent, reversible inhibitor of the gastric (H+/K+)-ATPase. In an anaesthetised lumen-perfused rat preparation, it inhibited pentagastrin-stimulated gastric acid secretion with intravenous and intraduodenal inhibitory ED50 values of 2.40 mumol/kg and 4.43 mumol/kg, respectively. In the conscious fistula rat model, doses of 10 mumol/kg IV and 25 mumol/kg PO produced mean peak inhibitions of basal acid output of 91% and 97%, respectively. In these experiments, the duration of action of SK&F 97574 was much shorter than that of the covalent (H+/K+)-ATPase inhibitor, omeprazole. In the conscious Heidenhain pouch dog, SK&F 97574 inhibited histamine-stimulated gastric acid secretion after both intravenous and oral administration with ED50 values of 0.49 mumol/kg and 0.89 mumol/kg, respectively. In this model, duration of action studies showed that significant residual inhibition of acid secretion remained 8 hours after intravenous dosing with SK&F 97574 (producing peak inhibition of 92%). However, 24 hours after oral dosing of SK&F 97574 (10 mumol/kg), no significant inhibition remained. These data indicate that the duration of action of SK&F 97574 is longer than that of the histamine H2 receptor antagonists such as cimetidine, but shorter than that of covalent (H+/K+)-inhibitors such as omeprazole. Overall, the pharmacological properties of SK&F 97574 suggest that it could be a potentially useful clinical treatment for acid-related diseases.
Parsons
M E
ME
SmithKline Beecham Research, The Frythe, Welwyn, Hertfordshire, UK.
Rushant
B
B
Rasmussen
T C
TC
Leach
C
C
Ife
R J
RJ
Postius
S
S
Pope
A J
AJ
D000634:Aminoquinolines / Q000494:pharmacology*; D000818:Animals; D000863:Antacids / Q000494:pharmacology; D001667:Binding, Competitive; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005744:Gastric Acid / Q000378:metabolism; D005747:Gastric Fistula / Q000503:physiopathology; D005750:Gastric Juice / Q000187:drug effects; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism; D006633:Histamine Antagonists / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D008297:Male; D009853:Omeprazole / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism / Q000494:pharmacology; D054328:Proton Pump Inhibitors; D051381:Rats; D017208:Rats, Wistar; D012636:Secretory Rate / Q000187:drug effects; D013270:Stomach / Q000201:enzymology*
D000634:Aminoquinolines; D000863:Antacids; D004791:Enzyme Inhibitors; D006633:Histamine Antagonists; D054328:Proton Pump Inhibitors; C069704:3-butyryl-4-(2-methylphenylamino)-8-methoxyquinoline; C084536:3-butyryl-4-(2-methylphenylamino)-8-(2-hydroxyethoxy)quinoline; D009853:Omeprazole; D011188:Potassium