Abstract

The disposition and metabolism of the new antihypertensive agent 2-(2"(1",3"-dioxolan-2-yl)-2-methyl-4-(2′-oxopyrrolidin-1-yl)-6-nitro-2H-1-benzopyran (SKP-450) were investigated in male rats after single oral and i.v. doses of ¹⁴C-labeled compound. After an oral 2.0 mg/kg dose, mean radiocarbon recovery was 98.2 ± 2.3% with 31.1 ± 7.3% in the feces and 67.1 ± 14.3% in the urine. Biliary excretion of radioactivity for the first 24-h period was approximately 40%, suggesting that SKP-450 is cleared either by hepatobiliary excretion or by renal excretion. SKP-450 was well absorbed; bioavailability calculated on the basis of radioactivity was 68 to 97%. Tissue distribution of the radioactivity was widespread with high concentrations in the liver and kidney but low central nervous system penetration. Radio-HPLC analysis of bile and urine from rats indicated the extensive metabolism of SKP-450 into oxidative metabolites. Oxidative metabolism of the dioxolanyl ring resulted in an aldehyde intermediate, subsequently confirmed in vitro, which was further oxidized to the corresponding carboxylic acid (M1) or reduced to the corresponding alcohol (M3). No parent drug was detected in the urine or bile. Glucuronide conjugate of M3 was also detected in urine and bile, accounting for 5.8 ± 2.1 and 8.9 ± 3.7% of the excreted radioactivity, respectively. Quantitative data obtained from plasma samples suggest that the majority of circulating radioactivity was associated with metabolites. Our results suggest that the long duration of pharmacological activity of SKP-450 (>10 h) is largely attributable to its metabolites.