title: Pharmacokinetics and metabolism of endothelin receptor antagonist: contribution of kidneys in the overall in vivo N-demethylation.
abstract: In vivo clearance of BMS-182874 was primarily due to metabolism via stepwise N-demethylation. Despite in vivo clearance approached ca 50% of the total liver plasma flow, BMS-182874 was completely bioavailable after oral administration in rats. Saturable first-pass metabolism and the role of extrahepatic tissue were evaluated as possible reasons for complete oral bioavailability despite extensive metabolic clearance. Pharmacokinetic parameters were obtained after an intravenous and a range of oral doses of BMS-182874 in rats. Bile and urine were collected from bile-duct cannulated (BDC) rats and the in vivo metabolic pathways of BMS-182874 were evaluated. Pharmacokinetics of BMS-182874 were also compared in nephrectomized (renally impaired) vs. sham-operated control rats. Oral bioavailability of BMS-182874 averaged 100%, indicating that BMS-182874 was completely absorbed and the first-pass metabolism (liver or intestine) was negligible. The AUC and Cmax values increased dose-proportionally, indicating kinetics were linear within the oral dose range of 13 to 290 mmole/kg. After intravenous administration of BMS-182874 to BDC rats, about 2% of intact BMS-182874 was recovered in excreta, indicating that BMS-182874 was cleared primarily via metabolism in vivo. The major metabolite circulating in plasma was the mono-N-desmethyl metabolite and the major metabolite recovered in excreta was the di-N-desmethyl metabolite. In vivo clearance of BMS-182874 was significantly reduced in nephrectomized rats. These observations suggest saturable first-pass metabolism is unlikely to be a mechanism for complete oral bioavailability of BMS-182874. Reduced clearance observed in the nephrectomized rats suggests that extrahepatic tissues (e.g., kidneys) may play an important role in the in vivo clearance of xenobiotics that are metabolized via N-demethylation.
authors.affiliation: Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543, USA. saeho.chong@bms.com
authors.forename: Saeho
authors.initials: S
authors.lastname: Chong
authors.forename: Mary
authors.initials: M
authors.lastname: Obermeier
authors.forename: W Griffith
authors.initials: WG
authors.lastname: Humphreys
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D019540:Area Under Curve; D003619:Dansyl Compounds / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D065128:Endothelin Receptor Antagonists; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008745:Methylation / Q000187:drug effects; D009392:Nephrectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000378:metabolism
chemical_list: D000959:Antihypertensive Agents; D003619:Dansyl Compounds; D065128:Endothelin Receptor Antagonists; D017466:Receptors, Endothelin; C085754:5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamide