Acid-promoted epimerization of arbaprostil, 15(R)-15-methylprostaglandin E2, elicits gastric antisecretory activities in rats.
Gastric acid antisecretory activities of 15(R)-15-methylprostaglandin E2 (arbaprostil) preincubated or not preincubated with 0.9% physiological saline, the pH of which was precisely adjusted to less than 4.30, were examined in pylorus-ligated rats, and compared with those of 15(S)-15-methylprostaglandin E2 (15(S), epimer of arbaprostil). 15(S), unlike arbaprostil without preincubation, when s.c.-administered to rats significantly inhibited gastric acid secretion in a dose-dependent manner (30-300 micrograms/kg). However, arbaprostil preincubated at 37 degrees C for 30 min with 0.9% saline, at pHs of 4.30, 2.75 and 1.20, respectively, showed the following order of pH-dependent antisecretory activities: 1.20 greater than 2.75 greater than 4.30. An increase in 15(S) formation from arbaprostil in a pH-dependent manner was also observed by radioisotopic experiments under the same incubation conditions using [3H]-labeled arbaprostil. The present result suggests that the gastric antisecretory effect of arbaprostil can be mainly explained in terms of the formation of 15(S) after oral administration.
Takanashi
H
H
Department of Pharmacology, Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan.
Kawabe
Y
Y
Akima
M
M
D000284:Administration, Oral; D000818:Animals; D001101:Arbaprostil / Q000008:administration & dosage* / Q000737:chemistry; D005744:Gastric Acid / Q000378:metabolism*; D005745:Gastric Acidity Determination; D006863:Hydrogen-Ion Concentration; D007279:Injections, Subcutaneous; D008297:Male; D011897:Random Allocation; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism
D001101:Arbaprostil