Lithium and Valproate Combined Administration: Acute Behavioural Effects and Drug Plasma Levels

Abstract

Drug plasma concentrations and behavioural effects of acute combined administration of lithium and valproic acid were studied in normonatraemic and hyponatraemic rats. Hyponatraemia was induced two hours before drug administration and behavioural observations lasted for two additional hours. Blood was collected by the end of the behavioural observation. The higher doses of valproic acid (360 mg/kg) or lithium (2 mEq/kg) induced more head-shakes and higher plasma concentration than 180 mg/kg of valproic acid or lithium 1 mEq/kg, respectively. Valproic acid and lithium administered separately induced more head shakes and higher drug plasma levels in hyponatraemic rats than in normonatraemic animals. Combined administration of valproic acid (180 mg/kg) and lithium (2 mEq/kg) produced a supra-aditive effect in head-shakes. The drug interaction between lithium and valproic acid induced a decrease in valproic acid plasma level and an increase in lithium plasma levels.

Effects of Lithium on the Pharmacokinetics of Valproate in Rats

“…Some investigators have reported that the combination of lithium and valproate induces a decrease in the plasma valproate level in rats (Vargas et al 1996), that lithium increases activities of cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) of liver microsomes in rats (Feuerstein et al 1979), and that valproate is metabolized mainly by UGT and partially by CYP in rats (Granneman et al 1984). From these reports, we assumed that the decrease in the plasma valproate level by lithium is caused by lithiuminduced activation of UGT or CYP (or both) in the liver microsomes, or possibly by increase in urinary excretion of valproate.…”

Monitoramento da adesão ao tratamento com lítio

“…A associação com o valproato resulta em interações farmacodinâmica e farmacocinética, com efeitos gastrointestinais e aumento de peso dos pacientes. É possível que essa interação seja clinicamente importante, visto que ocorrem alterações de parâmetros farmacocinéticos como: área sobre a curva e concentrações máxima e mínima, em que se observam aumentos de 11%, 12,4% e 7,3%, respectivamente, sendo o tempo de aparecimento da concentração máxima reduzido em 1,5 hora (Vargas et al, 1996).…”