title: Gastrointestinal first-pass effect of YJA-20379-8, a new reversible proton pump inhibitor, in rats.
abstract: Since low bioavailability of YJA-20379-8 (3-butyryl-4-[5-R-(+)-methylbenzylamino]-8ethoxy-1,7-naph thy ridine), 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 microg 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 AUC(0-24h) 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.
authors.affiliation: College of Pharmacy, Seoul National University, Kwanak-Gu, Korea.
authors.forename: J
authors.initials: J
authors.lastname: Kim
authors.forename: E J
authors.initials: EJ
authors.lastname: Kim
authors.forename: K S
authors.initials: KS
authors.lastname: Han
authors.forename: M S
authors.initials: MS
authors.lastname: Chang
authors.forename: M G
authors.initials: MG
authors.lastname: Lee
mesh_terms: D000818:Animals; D000897:Anti-Ulcer Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D001682:Biological Availability; D001835:Body Weight / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004064:Digestive System / Q000378:metabolism*; D006207:Half-Life; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism*; D008297:Male; D009287:Naphthyridines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D054328:Proton Pump Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C114511:3-butyryl-4-(5R-methylbenzylamino)-8-ethoxy-1,7-naphthyridine; D000897:Anti-Ulcer Agents; D009287:Naphthyridines; D054328:Proton Pump Inhibitors