In vivo induction of P-glycoprotein: impact on ivermectin gastrointestinal disposition

BALLENT, M.; LIFSCHITZ, A.; VIRKEL, G.; SALLOVITZ, J.; MATÉ, L.; LANUSSE, C.

Buenos Aires

Congreso; XL Reunión Anual de la Asociación Argentina de Farmacología Experimental; 2007

SAFE

Ivermectin (IVM), a broad-spectrum antiparasitic drug has been shown to be a substrate of the drug transporter P-glycoprotein (P-gp). The aim of current study was to assess the comparative effect of well-known enzyme inducer agents, rifampicin (RFP) and phenobarbital (FNB), on the intestinal P-gp activity-dependant   IVM disposition kinetics in rats. Male Wistar rats were allocated into three groups of 15 rats each. Animals were treated with RFP (Group B) (160 mg/day) or FNB (Group C) (30 mg/day), both orally administered during 8 days. After this period, untreated control (Group A) and pretreated animals received IVM (200µg/kg) subcutaneously. Animals were sacrificed between 6 and 72 h post-treatment. Blood and gastrointestinal tissues were collected and IVM concentrations measured by HPLC. The plasma and gastrointestinal disposition kinetics of IVM was unaffected by the presence of RFP. However, the pretreatment with FNB resulted in significantly lower IVM systemic concentrations compared to the IVM alone treatment. The peak plasma concentration and the systemic availability were between 149 and 164% lower in the FNB pretreated group. IVM intestinal secretion measured as the ratio between drug availability in the luminal content and gut wall tissues was significantly higher (90%) in the FNB pretreated rats. These preliminary results demonstrate that FNB drastically affects the IVM disposition kinetics, which is likely due to a strong induction of intestinal P-gp activity.