Disposition of the angiotensin II receptor antagonist L-158,809 in rats and rhesus monkeys

Drug Metab Dispos. 1994 Mar-Apr;22(2):183-8.

Abstract

The disposition of the angiotensin II receptor antagonist L-158,809 was studied in male rats and female rhesus monkeys. Rats were dosed either intravenously or orally with 0.3 mg [3H]L-158,809/kg. The terminal half-life of L-158,809 was 7.6 +/- 3.1 hr. Plasma clearance was 45.5 +/- 15.9 ml/hr/kg, and the volume of distribution at steady state was 0.37 +/- 0.11 liter/kg. The drug was completely bioavailable in rats. After oral administration, the peak plasma concentration of L-158,809 was 0.70 +/- 0.21 micrograms/ml at 15 min; only the parent drug was observed in plasma. After an oral dose of 3.0 mg [3H]L-158,809/kg, the peak plasma concentration of 4.9 +/- 0.6 micrograms/ml occurred at 1 hr. By 24 hr, 53.3 +/- 9.9% of an intraduodenal dose of 0.3 mg [3H]L-158,809/kg was excreted into bile. L-158,809 and its tetrazole-N2-beta-glucuronide were the major biliary components. Rhesus monkeys were dosed orally and intravenously at 1.0 mg and 0.5 mg [3H]L-158,809/kg, respectively. The plasma concentrations of L-158,809 varied considerably between monkeys after oral administration. The peak concentration was 42 +/- 42 ng/ml at 30 min, and the bioavailability was 32.3 +/- 12.6%. Plasma clearance was 839 +/- 364 ml/hr/kg; the volume of distribution at steady state was 1.42 +/- 0.73 liter/kg. Besides the parent, the major metabolite in monkey plasma was the tetrazole-N2-glucuronide of L-158,809. Both species excreted > 10% of the dose in the urine after intravenous or oral dosing; most of the dose was excreted in the feces, indicating extensive biliary excretion.

Publication types

  • Comparative Study

MeSH terms

  • Administration, Oral
  • Angiotensin II / metabolism*
  • Angiotensin Receptor Antagonists*
  • Animals
  • Bile / metabolism
  • Biological Availability
  • Blood Proteins / metabolism
  • Female
  • Glucuronates / metabolism
  • Half-Life
  • Imidazoles / pharmacokinetics*
  • Imidazoles / pharmacology
  • Injections, Intravenous
  • Macaca mulatta
  • Male
  • Protein Binding
  • Rats
  • Rats, Sprague-Dawley
  • Tetrazoles / pharmacokinetics*
  • Tetrazoles / pharmacology
  • Tissue Distribution

Substances

  • Angiotensin Receptor Antagonists
  • Blood Proteins
  • Glucuronates
  • Imidazoles
  • Tetrazoles
  • Angiotensin II
  • L 158809