Lipophilicity and disposition of 1-aryl-piperazines in the rat

Abstract

1. The disposition of eight 1-aryl-piperazines was investigated in rats after i.v. administration. The concentration of 1-aryl-piperazine in body fluids and tissues was determined by h.p.l.c. or electron-capture g.l.c. Correlations of kinetics and physiological parameters with the lipophilicity of each 1-aryl-piperazine, determined by h.p.l.c. retention on a reverse-phase C₁₈ column at neutral pH, were investigated.

2. Binding to rat plasma proteins varied within the series, increasing with lipophilicity. For the majority of the derivatives the blood-to-plasma ratio was close to unity, implying an almost equal distribution between erythrocytes and plasma. The most lipophilic 1-aryl-piperazine of the series partitioned more into erythrocytes.

3. The eight compounds differed widely in V_ss and total Cl values and as a general trend both values increased with lipophilicity. The percentage of the dose excreted unchanged in the urine decreased progressively with increasing lipophilicity.

4. 1-Aryl-piperazines were distributed extensively in all the tissues examined, concentrating particularly in the eliminating organs and lung. They easily entered the rat brain, C_max values generally being reached within five minutes of parenteral injection. 1-Aryl-piperazine brain uptake increased with lipophilicity.