First-Pass Metabolism of ONO-5046 (N-[2-[4-(2, 2-Dimethylpropionyloxy)phenylsulfonylamino]benzoyl]-aminoacetic Acid), a Novel Elastase Inhibitor, in Rats

• Published in: Biological & pharmaceutical bulletin Vol. 20; no. 4; pp. 392 - 396
• Main Authors: WATANABE, Fumiko, SATO, Masahiko, KATO, Akiko, MURAKAMI, Teruo, HIGASHI, Yutaka, YATA, Noboru
• Format: Journal Article
• Language: English
• Published: Tokyo The Pharmaceutical Society of Japan 01.04.1997; Maruzen; Japan Science and Technology Agency
• Subjects: Animals; Biological and medical sciences; Biological Availability; Duodenum; elastase inhibitor; first-pass metabolism; General and cellular metabolism. Vitamins; Glycine - administration & dosage; Glycine - analogs & derivatives; Glycine - metabolism; Glycine - pharmacokinetics; hepatic extraction ratio; Injections, Intravenous; intestinal first-pass metabolism; Intestinal Mucosa - metabolism; Liver - metabolism; Male; Medical sciences; ONO-5046; Pancreatic Elastase - antagonists & inhibitors; Pharmacology. Drug treatments; Portal Vein; rat; Rats; Rats, Wistar; Serine Proteinase Inhibitors - administration & dosage; Serine Proteinase Inhibitors - metabolism; Serine Proteinase Inhibitors - pharmacokinetics; Sulfonamides - administration & dosage; Sulfonamides - metabolism; Sulfonamides - pharmacokinetics; Leukocyte elastase; Serine endopeptidases; Rat; Enzyme; Digestive system; Liver; Rodentia; Gut; Oral administration; Enzyme inhibitor; Metabolism; Peptidases; Vertebrata; Mammalia; Animal; First pass effect; Hydrolases; Pharmacokinetics
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.20.392

The first-pass metabolism in the intestine and liver of ONO-5046 (N-[2-[4-(2, 2-dimethylpropionyloxy)phenylsulfonylamino]benzoyl]aminoacetic acid), a newly synthesized elastate inhibitor, was separately estimated in rats. When ONO-5046 solution was administered into the whole intestine via the bile duct at a dose of 5 μmol/rat, the extent of bioavailability was only 1.5%. A small but significant increase in the bioavailability with an increase in the dose suggested marked first-pass metabolism with a saturable process. Hepatic first-pass metabolism was estimated by determining the hepatic extraction ratio of ONO-5046 after administration into the portal vein at two different infusion rates (5 μmol/kg/9 min or 5 μmol/kg/20 s). The extraction ratio was relatively small and constant (about 20%) under 2 different infusion rates of the drug. Intestinal first-pass metabolism was estimated by determining the drug recovery in the measenteric plasma after administering the drug into the intestinal loop in situ (mesenteric blood collecting method in situ). The recovery percentage of ONO-5046 in the mesenteric plasma was small (2.58±0.04% at a dose of 1 μmol/rat), and the remaining ONO-5046 recovered in the mesenteric plasma and in the intestinal loop was a metabolite of ONO-5046 (EI-601, N-[2-[(4-hydroxyphenyl)sulfonylamino]benzoyl]aminoacetic acid). Recovery percentage of ONO-5046 in the mesenteric plasma increased significantly with an increase in the dose, although the recovery percentage was still low, even at a higher dose (9.55±1.17% of dose at a dose of 5 μmol/rat). These results indicate that the low oral bioavailability of ONO-5046 in vivo is mainly due to the marked intestinal first-pass metabolism, including the metabolism in the intestinal fluid, and the dose-dependent oral bioavailability was derived from the saturable intestinal first-pass metabolism.