title: Pretreatment with the inducers rifampicin and phenobarbital alters ivermectin gastrointestinal disposition.
abstract: The goal of the study was to evaluate the effects of rifampicin (RFP) and phenobarbital (PBT) on the plasma and gastrointestinal disposition kinetics of ivermectin (IVM) subcutaneously administered to Wistar rats. Fifty seven rats were used. Animals in Group I were the noninduced (control) group. Those in Groups II and III received a treatment with RFP (160 mg/day) and PBT (35 mg/day), respectively, both given orally during eight consecutive days as induction regimen. The IVM pharmacokinetic study was started 24 h after the RFP and PBT last administration. Animals received IVM (200 microg/kg) by subcutaneous injection. Rats were sacrificed between 6 h and 3 days after IVM administration. Blood and samples of liver tissue, intestinal wall and luminal content of jejunum were collected from each animal. IVM concentrations were measured by high performance liquid chromatography. IVM disposition kinetics in plasma and tissues was significantly modified by the PBT treatment, but not by RFP. Despite the enhanced CYP3A activity observed after the pretreatment with RPF and PBT, there were no marked changes on the percentages of IVM metabolites recovered from the bloodstream in induced and noninduced animals. An enhanced P-glycoprotein-mediated intestinal transport activity in pretreated animals (particularly in PBT pretreated rats) may explain the drastic changes observed on IVM disposition.
authors.affiliation: Laboratorio de Farmacología Veterinaria, Facultad de Ciencias Veterinarias, Universidad Nacional del Centro de la Provincia de Buenos Aires, Campus Universitario, 7000 Tandil, Argentina.
authors.forename: M
authors.initials: M
authors.lastname: Ballent
authors.forename: A
authors.initials: A
authors.lastname: Lifschitz
authors.forename: G
authors.initials: G
authors.lastname: Virkel
authors.forename: L
authors.initials: L
authors.lastname: Mate
authors.forename: C
authors.initials: C
authors.lastname: Lanusse
mesh_terms: D000818:Animals; D000977:Antiparasitic Agents / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000378:metabolism*; D007422:Intestines / Q000737:chemistry; D007559:Ivermectin / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics*; D008099:Liver / Q000737:chemistry; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012293:Rifampin / Q000494:pharmacology*
chemical_list: D000977:Antiparasitic Agents; D007559:Ivermectin; D051544:Cytochrome P-450 CYP3A; D012293:Rifampin; D010634:Phenobarbital