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

Abstract

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. 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. The eight compounds differed widely in Vss 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. 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, Cmax values generally being reached within five minutes of parenteral injection. 1-Aryl-piperazine brain uptake increased with lipophilicity.

Desenvolvimento de uma metodologia analítica por LC-MS/MS para determinação de meta-clorofenilpiperazina em plasma de camundongos submetidos à privação de sono paradoxal

“…Isto indica que podem ser encontradas elevadas concentrações do fármaco no plasma de indivíduos submetidos à administração de comprimidos com mCPP. Este achado corrobora os dados da _____________________________________________________________________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________________________________________________________________ literatura que apontam a grande variabilidade das concentrações circulantes (CACCIA et al, 1987;GIJSMAN et al, 1998).…”

“…Após administração oral de uma dose do fármaco (0,5 mg.kg -1 ) a concentração plasmática máxima (C max ) é de 30,8 ng.mL -1 (MAES et al, 2001;FEUCHTL et al, 2004). (FULLER et al, 1981;CACCIA et al, 1987;GARATTINI, 1990). STAACK et al, 2007;DICKSON et al, 2010), assim como do principal metabólito sob a forma livre MAURER, 2003MAURER, , 2005 Decorrida 24 horas após a sua administração, a presença da mCPP na urina é de 0,5% da dose administrada (CACCIA et al, 1987).…”

“…(FULLER et al, 1981;CACCIA et al, 1987;GARATTINI, 1990). STAACK et al, 2007;DICKSON et al, 2010), assim como do principal metabólito sob a forma livre MAURER, 2003MAURER, , 2005 Decorrida 24 horas após a sua administração, a presença da mCPP na urina é de 0,5% da dose administrada (CACCIA et al, 1987). Na Figura 4 está esquematizada a formação dos metabólitos da mCPP no organismo de ratos.…”