Disposition of DMP 811 (L-708,404), a potent angiotensin II receptor antagonist, in the rat, monkey, and chimpanzee.

DMP 811 {4-ethyl-2-n-propyl-1-[(2'-(1H-tetrazole-5-yl)biphenyl-4-yl) methyl]imidazole-5-carboxylic acid; L-708,404} is a highly potent angiotensin II receptor antagonist. The physiological disposition of DMP 811 was examined in the Sprague-Dawley rat, rhesus monkey, and pan troglodytes chimpanzee. Plasma concentrations of DMP 811 were determined by an HPLC assay with fluorescence detection. After intravenous administration of DMP 811 to rats (1 mg/kg), monkeys (0.5 mg/kg), and chimpanzees (0.5 mg/kg), the plasma clearance was 1.3, 1.8, and 0.3 ml/min/kg, respectively. The corresponding volumes of distribution were 0.16, 0.10, and 0.10 liters/kg, and the value for the terminal half-life was 3.0, 2.4, and 10.1 hr in the respective species. After oral administration to rats (5 mg/kg), monkeys (2 mg/kg), and chimpanzees (2 mg/kg), DMP 811 was 8.4%, 10.2%, and 8.0% bioavailable, respectively. The mass balance of [14C]DMP 811 was investigated in rats and monkeys. In rats, the radiolabeled dose was excreted primarily in feces (79% intravenous; 99% oral) with <1% of the dose in urine. In monkeys, the intravenous radiolabeled dose was excreted in both urine (48%) and feces (42%), whereas the oral dose was excreted largely in feces (79%), with an additional 6% in urine. In summary, DMP 811 was cleared slowly in all three species. The oral bioavailability of DMP 811 was low, but consistent across species. Pharmacokinetic data suggest that the low oral bioavailability was not caused by first-pass metabolism, but probably caused by limited absorption.