Sex-related differences in the gastrointestinal disposition of ivermectin in the rat: P-glycoprotein involvement and itraconazole modulation.
Ivermectin (IVM), a macrocyclic lactone used as antiparasite agent, has been reported as a P-glycoprotein (P-gp) substrate. The participation of P-gp in the IVM excretion process has been previously demonstrated. Sex-related differences in the kinetic behaviour of some macrocyclic lactone compounds have been observed. The aim of this work was to characterize in-vivo the comparative gastrointestinal disposition of IVM in male and female rats. The sex-related influence on the itraconazole (ITZ) modulation of P-gp-mediated IVM intestinal transport was also assessed. Sixty Wistar rats (30 male, 30 female) received IVM alone or co-administered with ITZ. Rats were killed between 6 and 72 h after treatment and blood, gastrointestinal tissues and lumen contents were collected. IVM concentrations were determined by high performance liquid chromatography. Substantial sex-related differences in the IVM disposition kinetics were observed. Higher IVM systemic availability was observed in female rats. The ITZ-mediated modulation of the IVM disposition kinetics had a differential impact between male and female rats. Co-administration with ITZ resulted in a marked increase in the IVM concentrations in the wall tissue from different portions of the gastrointestinal tract of male rats. The presence of ITZ induced drastic sex-related changes on the P-gp-mediated IVM gastrointestinal disposition.
Lifschitz
A
A
Laboratorio de Farmacología, Departamento de Fisiopatología, Facultad de Ciencias Veterinarias, Universidad Nacional del Centro, Tandil, Argentina. adrianl@vet.unicen.edu.ar
Ballent
M
M
Virkel
G
G
Sallovitz
J
J
Lanusse
C
C
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D000981:Antiprotozoal Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D004347:Drug Interactions; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism*; D017964:Itraconazole / Q000494:pharmacology*; D007559:Ivermectin / Q000493:pharmacokinetics*; D008297:Male; D051381:Rats; D017208:Rats, Wistar
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000935:Antifungal Agents; D000981:Antiprotozoal Agents; D017964:Itraconazole; D007559:Ivermectin