METABOLISM OF AZETIRELIN, A NEW THYROTROPIN-RELEASING-HORMONE (TRH) ANALOG, BY INTESTINAL MICROORGANISMS

Purpose. We evaluated the effect of luminal bacterial metabolism an in testinal absorption of azetirelin in rats. In vitro characteristics of bacterial metabolism of azetirelin were also investigated with the go al of overcoming the low stability of the peptidic drug against lumina l microorganisms. Methods. Plasma azetirelin levels after oral adminis tration to antibiotic-pretreated rats was examined. In vitro incubatio n experiments with bacterial suspensions were also performed to clarif y the location of azetirelin breakdown activity as well as the effects of oxygen, pH, and various protease inhibitors on drug metabolism. Re sults. Plasma azetirelin levels were sustained after oral administrati on to antibiotic-treated rats. Incubation with rat luminal contents de monstrated that azetirelin was metabolized by anaerobic bacteria, whic h are predominant in the distal intestine. Fecal suspensions from rats . dogs, and humans showed comparable metabolic activity, Azetirelin br eakdown in the bacterial suspension was pH-dependent and was inhibited in the presence of bacitracin or puromycin. Conclusions. Bacterial me tabolism influences the degree of absorption of azetirelin in the dist al intestine. Control of the luminal pH environment may be a practical method far improving the stability of azetirelin against intestinal m icroorganisms.