Pharmacokinetics and metabolism of endothelin receptor antagonist: contribution of kidneys in the overall in vivo N-demethylation

Arch Pharm Res. 2003 Jan;26(1):89-94. doi: 10.1007/BF03179938.


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.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Antihypertensive Agents / chemistry
  • Antihypertensive Agents / metabolism
  • Antihypertensive Agents / pharmacokinetics
  • Area Under Curve
  • Dansyl Compounds / chemistry
  • Dansyl Compounds / metabolism
  • Dansyl Compounds / pharmacokinetics*
  • Endothelin Receptor Antagonists*
  • Kidney / metabolism*
  • Male
  • Methylation / drug effects
  • Nephrectomy
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Endothelin / metabolism


  • Antihypertensive Agents
  • Dansyl Compounds
  • Endothelin Receptor Antagonists
  • Receptors, Endothelin
  • 5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamide