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

Arzneimittel-Forschung
Jawahar Lal, R C Gupta

Abstract

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 phenomeno...Continue Reading

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