Absorption, protein binding, pharmacokinetics and excretion of the anti-ischemic and anti-hypertensive arylpiperazine derivative CDRI-93/478 in rats

CDRI-93/478 (1- 4-(4-fluorophenyl) piperazine-1-yl]-3-(2-oxopyrrolidin-1-yl) propane hydrochloride, an arylpiperazine derivative, is a potent anti-ischemic and anti-hypertensive agent and is in advanced stage of preclinical trials. In order to develop CDRI-93/478 into a clinical agent, the absorption, protein binding, pharmacokinetics, and excretion of the compound were investigated in male Sprague-Dawley rats. Oral absorption was evaluated in situ and in vivo, using the portal-venous concentration difference method. The compound showed negligible absorption (ka = 0.01 h(-1)) at pH 2.6. However, the rate of absorption of the compound at pH 7.4 was 0.6 h(-1) and was comparable to that observed in the in vivo study (ka, >0.58 h(-1)) in rats after a single 2 mg/kg oral dose. In vitro and in vivo protein binding studies using the ultrafiltration method showed that the compound was subject to low protein binding (<40%) and was independent of the substrate concentration over a range of 1-16 microg/ml. Pharmacokinetic parameters of the compound were determined after intravenous and oral administration of 0.6, 2 and 8 mg/kg doses using a model independent method. After oral administration, the compound showed the double-peak phenomenon, which could be due to the high water solubility (log P, 1.01 +/- 0.01), regional differences in the gastrointestinal absorption and enterohepatic recirculation effects. The absorption of CDRI-93/478 was rapid and showed a bioavailability of 69.9 +/- 5.1% (mean +/- S. D.) after 2 and 8 mg/kg oral dose. However, the pharmacokinetic parameters of the compound could not be determined after the 0.6 mg/kg oral dose due to insufficient data points. The studies following intravenous and oral administration demonstrated linear pharmacokinetics, low clearance and high volume of distribution over the dose range studied. The excretion studies after the 8 mg/kg oral dose indicated that the compound was not excreted through the feces and the urinary excretion was very low (<2%).