P-glycoprotein in vivo induction evaluation: effect on ivermectin gastrointestinal disposition

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

Capital Federal

Congreso; XXXIX Reunión anual de la Asociación Argentina de Farmacología Experimental (SAFE); 2007

Asociación Argentina de Farmacología Experimental

Ivermectin (IVM), a broad-spectrum antiparasitic drug has been shown to be a substrate of the drug transport P-glycoprotein (P-gp). The aim of the study was to assess the comparative effect of rifampicin (RFP) and phenobarbital (FNB) as inducers of intestinal P-gp activity on the disposition kinetic of IVM subcutaneously (SC) administered in rats. Male Wistar rats were allocated into three groups of fifteen rats each. Animals were treated with RFP (Group B) or FNB (Group C) (160 and 30 mg per day, orally administered during 8 days). After this period, control (Group A) and pretreated animals received IVM (200µg/Kg) by SC route. 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 concentration 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 the availability in the gastrointestinal content and wall tissues were significantly higher (90 %) in the FNB pretreated rats. These preliminary results corroborate that FNB appears as a strong inducer of gastrointestinal P-gp affecting the kinetic disposition of parenteral administered drugs.