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

The American Society for Pharmacology and Experimental Therapeutics

Año: 2006 vol. 34 p. 457 - 462

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 atequimolar doses in the rat. Furthermore, the influence of both P-gpmodulator agents on the disposition kinetics of IVM in plasma,liver, and gastrointestinal tissues was characterized. For the invitro experiments, ileal sacs were incubated with IVM (3
M) in thepresence or absence of either ITZ (10
M) or PSC833 (10
M). Inthe in vivo experiments, male Wistar rats were randomly allocatedto three groups (n  18) and subcutaneously treated with IVM (200
g/kg1), alone and coadministered with ITZ (5 mg, two doses) orPSC833 (8.6 mg, two doses). Animals were sacrificed between 6and 96 h. Blood, liver, and gastrointestinal samples were collected.IVM concentrations were determined by high performance liquidchromatography. The rate of IVM accumulation in the intestinalwall of everted sacs was significantly higher after its incubationwith ITZ (0.115 nmol/g/min) and PSC833 (0.238 nmol/g/min) thanthat obtained after the incubation without the P-gp modulators(0.016 nmol/g/min). In agreement with the in vitro experiment, thepresence of ITZ and PSC833 induced an enhancement in the concentrationsof 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 tothe intestinal secretion of IVM.