“Modulation of the P-glycoprotein-mediated intestinal secretion of ivermectin: in vitro and in vivo assessments”.

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

Drug Metabolism and Disposition

AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS

Año: 2006 p. 457 - 463

0090-9556

The everted gut sac method was used to assess the role of the P-glycoprotein (P-gp) on the intestinal secretion of ivermectin (IVM), an antiparasitic widely used in human and veterinary medicine. The work included the evaluation of two different P-gp modulators (itraconazole and PSC833) used at equimolar doses in the rat. Furthermore, the influence of both P-gp modulator agents on the disposition kinetics of IVM in plasma, liver and gastrointestinal tissues was characterised. For the in vitro experiments, ileal sacs were incubated with IVM (3 µM) in the presence or absence of either itraconazole (ITZ) (10 µM) or PSC833 (10 µM). In the in vivo experiments, male Wistar rats were randomly allocated in three groups (n=18) and subcutaneously treated with IVM (200 µg/Kg-1) alone and co-administered with ITZ (5 mg, two doses) or PSC833 (8.6 mg, two doses). Animals were sacrificed between 6 and 96 h. Blood, liver and gastrointestinal samples were collected. IVM concentrations were determined by HPLC. The rate of IVM accumulation in the intestinal wall of everted sacs was significantly higher after its incubation with ITZ (0.115 nmol/g/min) and PSC833 (0.238 nmol/g/min) than that obtained after the incubation without the P-gp modulators (0.016 nmol/g/min). In agreement with the in vitro experiment, the presence of ITZ and PSC833 induced an enhancement in the concentrations of IVM in plasma and gastrointestinal tissues. The results obtained in the current work, both under in vivo and in vitro conditions, confirm the relevance of P-gp-mediated transport on the intestinal secretion of IVM.