title: Modulation of biotransformation systems and ABC transporters by benznidazole in rats.
abstract: The effect of antichagasic benznidazole (BZL; 100 mg/kg body weight/day, 3 consecutive days, intraperitoneally) on biotransformation systems and ABC transporters was evaluated in rats. Expression of cytochrome P-450 (CYP3A), UDP-glucuronosyltransferase (UGT1A), glutathione S-transferases (alpha glutathione S-transferase [GST-α], GST-μ, and GST-π), multidrug-resistance-associated protein 2 (Mrp2), and P glycoprotein (P-gp) in liver, small intestine, and kidney was estimated by Western blotting. Increases in hepatic CYP3A (30%) and GST-μ (40%) and in intestinal GST-α (72% in jejunum and 136% in ileum) were detected. Significant increases in Mrp2 (300%) and P-gp (500%) proteins in liver from BZL-treated rats were observed without changes in kidney. P-gp and Mrp2 were also increased by BZL in jejunum (170% and 120%, respectively). In ileum, only P-gp was increased by BZL (50%). The activities of GST, P-gp, and Mrp2 correlated well with the upregulation of proteins in liver and jejunum. Plasma decay of a test dose of BZL (5 mg/kg body weight) administered intraduodenally was faster (295%) and the area under the concentration-time curve (AUC) was lower (41%) for BZL-pretreated rats than for controls. The biliary excretion of BZL was higher (60%) in the BZL group, and urinary excretion of BZL did not show differences between groups. The amount of absorbed BZL in intestinal sacs was lower (25%) in pretreated rats than in controls. In conclusion, induction of biotransformation enzymes and/or transporters by BZL could increase the clearance and/or decrease the intestinal absorption of coadministered drugs that are substrates of these systems, including BZL itself.
authors.affiliation: Instituto de Fisiología Experimental (CONICET)-Area Fisiología, Facultad de Ciencias Bioquímicas y Farmacéuticas (UNR), Rosario, Argentina.
authors.forename: Virginia G
authors.initials: VG
authors.lastname: Perdomo
authors.forename: Juan P
authors.initials: JP
authors.lastname: Rigalli
authors.forename: Silvina S M
authors.initials: SS
authors.lastname: Villanueva
authors.forename: María L
authors.initials: ML
authors.lastname: Ruiz
authors.forename: Marcelo G
authors.initials: MG
authors.lastname: Luquita
authors.forename: Claudia G
authors.initials: CG
authors.lastname: Echenique
authors.forename: Viviana A
authors.initials: VA
authors.lastname: Catania
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D015870:Gene Expression / Q000187:drug effects; D005982:Glutathione Transferase / Q000378:metabolism; D007408:Intestinal Absorption / Q000187:drug effects; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D009593:Nitroimidazoles / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D007527:Isoenzymes; D009593:Nitroimidazoles; D005982:Glutathione Transferase; C119995:glutathione S-transferase alpha; C009999:benzonidazole