Pharmacokinetics of DA‐8159, a New Erectogenic, after Intravenous and Oral Administration to Rats: Hepatic and Intestinal First‐Pass Effects

Abstract

The purposes of this study were to report dose‐independent (after intravenous administration) and dose‐dependent (after oral administration) area under the curve of plasma concentration versus time from time zero to time infinity (AUC), and gastric, intestinal, and/or hepatic first‐pass effects (after intravenous, intraportal, intragastric, and intraduodenal administration) of DA‐8159 [5‐[2‐propyloxy‐5‐(1‐methyl‐2‐pyrollidinylethylamidosulfonyl)phenyl]‐1‐methyl‐3‐propyl‐1,6‐dihydro‐7H‐pyrazolo(4,3‐d)pyrimidine‐7‐one], a new erectogenic, in rats. After intravenous administration at doses of 5, 10, and 30mg/kg, the AUCs and time‐averaged total body clearances (CLs) were dose‐independent. However, the AUCs were dose‐dependent after oral administration at doses of 20, 30, 50, and 100mg/kg. This result could be due to saturation of first‐pass effects at high doses. The extent of absolute oral bioavailability (F) of DA‐8159 was 38.0% at a dose of 30mg/kg. Considering almost complete absorption of DA‐8159 from rat gastrointestinal tract (∼99% of oral dose of 30mg/kg), the low F could be due to considerable hepatic, gastric, and/or intestinal first‐pass effects. After intravenous administration at three doses, the CLs were considerably slower than the reported cardiac output in rats, suggesting almost negligible first‐pass effect of DA‐8159 in the heart and lung. The AUCs were not significantly different between intragastric and intraduodenal administration of DA‐8159 at a dose of 30mg/kg (131 and 127 μg · min/mL), suggesting that gastric first‐pass effect of DA‐8159 was almost negligible in rats. However, the values were significantly smaller than that after intraportal administration (311 μg · min/mL), indicating considerable intestinal first‐pass effect of DA‐8159 in rats of ∼58% of the oral dose. Approximately 23% of DA‐8159 at a dose of 30mg/kg absorbed into the portal vein was eliminated by the liver (hepatic first‐pass effect) based on AUC difference between intravenous and intraportal administration (the value, 23%, was equivalent to ∼9.6% of oral dose). The low F of DA‐8159 after oral administration at a dose of 30mg/kg to rats was mainly due to considerable intestinal (∼58%) first‐pass effects. © 2003 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:2185–2195, 2003