Metabolism of azetirelin, a new thyrotropin-releasing hormone (TRH) analogue, by intestinal microorganisms.
OBJECTIVE
We evaluated the effect of luminal bacterial metabolism on intestinal absorption of azetirelin in rats. In vitro characteristics of bacterial metabolism of azetirelin were also investigated with the goal of overcoming the low stability of the peptidic drug against luminal microorganisms.


METHODS
Plasma azetirelin levels after oral administration to antibiotic-pretreated rats was examined. In vitro incubation experiments with bacterial suspensions were also performed to clarify the location of azetirelin breakdown activity as well as the effects of oxygen, pH, and various protease inhibitors on drug metabolism.


RESULTS
Plasma azetirelin levels were sustained after oral administration to antibiotic-treated rats. Incubation with rat luminal contents demonstrated that azetirelin was metabolized by anacrobic bacteria, which are predominant in the distal intestine. Fecal suspensions from rats, dogs, and humans showed comparable metabolic activity. Azetirelin breakdown in the bacterial suspension was pH-dependent and was inhibited in the presence of bacitracin or puromycin.


CONCLUSIONS
Bacterial metabolism influences the degree of absorption of azetirelin in the distal intestine. Control of the luminal pH environment may be a practical method for improving the stability of azetirelin against intestinal microorganisms.
Sasaki
I
I
Novel Pharma Laboratories, Yamanouchi Pharmaceutical Co., Ltd., Shizuoka, Japan.
Tamura
T
T
Shibakawa
T
T
Fujita
T
T
Murakami
M
M
Yamamoto
A
A
Muranishi
S
S
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001384:Azetidines / Q000378:metabolism*; D002432:Cecum / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D004064:Digestive System / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology*; D004151:Dipeptides / Q000378:metabolism*; D004285:Dogs; D004355:Drug Stability; D005243:Feces / Q000382:microbiology; D006207:Half-Life; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption / Q000187:drug effects; D008297:Male; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity
D000900:Anti-Bacterial Agents; D001384:Azetidines; D004151:Dipeptides; D011480:Protease Inhibitors; C054995:azetirelin