First-pass metabolism of gentisamide: influence of intestinal metabolism on hepatic formation of conjugates. Studies in the once-through vascularly perfused rat intestine-liver preparation.
Gentisamide (GAM) metabolism was studied in a once-through in situ perfused rat intestine-liver preparation in a manner which mimicked the first-pass effect. GAM (2.56 to 392 microM) was delivered into the intestine via the superior mesenteric artery at a flow of 7.5 ml/min. The intestinal venous outflow into the portal vein and the hepatic arterial flow (2.5 ml/min; without drug) served as dual inflows into the liver. The steady state intestinal extraction ratios (E1, 0.33 to 0.06) and hepatic extraction ratios (EH, 0.84 to 0.37) were highly concentration dependent, decreasing with increasing GAM concentrations. Gentisamide-5-glucuronide was found to be the major intestinal metabolite, and gentisamide-2-sulfate was also formed, albeit to a much lesser extent. However, hepatic metabolism of GAM revealed 5-sulfation and glucuronidation as the predominant pathways, with GAM 2-sulfation as a minor pathway. About 1 to 3% and 7% of dose was excreted into lumen and bile, respectively, mostly as GAM-5G. From the metabolic data, the fitted parameters confirmed that more enzymes exist in the liver than in intestine for the processing of GAM. The Km for 2-sulfation by the intestine was higher than the apparent Kms observed for 2- and 5-sulfation in liver. However, the Kms for 5-glucuronidation for both the intestine and liver were similar. The interrelationship between intestine and liver formation of first-pass metabolites showed that, at low GAM input concentration entering the IL preparation, the intestine, being the anterior organ, regulated the available substrate for hepatic elimination, and hence reduced the contribution of hepatic metabolism in the overall first-pass effect.(ABSTRACT TRUNCATED AT 250 WORDS)
Hirayama
H
H
Faculty of Pharmacy, University of Toronto, Ontario, Canada.
Pang
K S
KS
D000818:Animals; D001549:Benzamides / Q000378:metabolism* / Q000493:pharmacokinetics; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains
D001549:Benzamides; C055881:gentisamide