PT  - JOURNAL ARTICLE
AU  - M. Ballent
AU  - A. Lifschitz
AU  - G. Virkel
AU  - J. Sallovitz
AU  - C. Lanusse
TI  - MODULATION OF THE P-GLYCOPROTEIN-MEDIATED INTESTINAL SECRETION OF IVERMECTIN: IN VITRO AND IN VIVO ASSESSMENTS
AID  - 10.1124/dmd.105.007757
DP  - 2006 Mar 01
TA  - Drug Metabolism and Disposition
PG  - 457--463
VI  - 34
IP  - 3
4099  - http://dmd.aspetjournals.org/content/34/3/457.short
4100  - http://dmd.aspetjournals.org/content/34/3/457.full
SO  - Drug Metab Dispos2006 Mar 01; 34
AB  - 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 (ITZ) and valspodar (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 characterized. For the in vitro experiments, ileal sacs were incubated with IVM (3 μM) in the presence or absence of either ITZ (10 μM) or PSC833 (10 μM). In the in vivo experiments, male Wistar rats were randomly allocated to three groups (n = 18) and subcutaneously treated with IVM (200 μg/kg–1), alone and coadministered 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 high performance liquid chromatography. 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 to the intestinal secretion of IVM. The American Society for Pharmacology and Experimental Therapeutics