Gastrointestinal First-pass Effect of YJA-20379-8, a New Reversible Proton Pump Inhibitor, in Rats

Abstract

Abstract Since low bioavailability of YJA-20379-8 (3-butyryl-4-[5-R-(+)-methylbenzylamino]-8-ethoxy-1, 7-naphthyridine), a new reversible proton pump inhibitor, has been reported after oral administration of the drug to rats, the first-pass organ of the drug was investigated in rats. YJA-20379-8, 50 mg kg−1, was infused over 1 min via the jugular vein (n = 5) or the portal vein (n = 5), or was instilled directly into the stomach (n = 5) or the duodenum (n = 5). After intravenous or intraportal infusion of the drug, the total body clearance of YJA-20379-8 (18.1 and 19.7 mL min−1 kg−1 based on plasma data) was considerably lower than the reported cardiac output (296 mL min−1 kg−1 based on blood data) in rats. This data indicated that the first-pass effect of YJA-20379-8 by the lung and heart was negligible. The areas under the plasma concentration-time curve from time zero to time infinity (AUC) after intravenous or intraportal administration of YJA-20379-8 (2760 and 2540 μg min mL−1) were not significantly different, indicating that the hepatic first-pass effect of the drug was also negligible in rats. After intragastric or intraduodenal instillation of YJA-20379-8, the extent of absolute oral bioavailability was 18.2 and 33.8%, respectively. Based on gastrointestinal recovery studies, approximately 86.5 and 91.2% of YJA-20379-8 was absorbed from rat gastrointestinal tract after intragastric or intraduodenal instillation, respectively. The data indicated that gastrointestinal and intestinal first-pass effects of YJA-20379-8 were approximately 68% (86.5–18.2) and 57% (91.2–33.8), respectively. The AUC0-24h values of YJA-20379-8 were significantly different between intragastric and intraduodenal instillation, indicating that the gastric first-pass effect of the drug was approximately 10% in rats. Therefore, it could be concluded that the low F value of YJA-20379-8 after oral administration of the drug could be due to a considerable (approx. 60%) intestinal first-pass effect in rats.