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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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

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.[1]


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