title: In Vitro and In Vivo Mechanistic Studies toward Understanding the Role of 1-Aminobenzotriazole in Rat Drug-Drug Interactions.
abstract: 1-Aminobenzotriazole (ABT) is regularly used in vivo as a nonspecific and irreversible cytochrome P450 inhibitor to elucidate the role of metabolism on the pharmacokinetic profile of xenobiotics. However, few reports have considered the recent findings that ABT can alter drug absorption or have investigated the possible differential inhibition of ABT on intestinal and hepatic metabolism. To address these uncertainties, pharmacokinetic studies under well controlled and defined ABT pretreatment conditions (50 mg/kg, 1 hour ABT i.v. and 16 hours ABT p.o.) were conducted prior to the oral administration of metoprolol, a permeable P450 probe that undergoes extensive intestinal and hepatic metabolism. The pharmacokinetic profile of metoprolol was affected differently by the two ABT pretreatments. An increase in area under the curve of 16-fold with ABT p.o. and 6.5-fold with ABT i.v. was observed compared with control. Based on in vitro studies, this difference could not be attributed to a differential inhibition of intestinal and hepatic metabolism. In the ABT i.v. pretreatment group, the increase in area under the curve was also associated with a prolonged time at maximal concentration (24-fold versus control), suggesting a delay in absorption. This was further confirmed by the administration of a charcoal meal, which resulted in a 7-fold increase in stomach weights in the 1-hour ABT pretreated groups compared with the untreated or 16-hour ABT pretreated rats. Based on these results, we recommend pretreating rats with ABT p.o. 16 hours before the administration of a test compound to preserve the inhibitory effect on intestinal and hepatic metabolism and avoid the confounding effect on drug absorption.
authors.affiliation: Service de Néphrologie et Centre de Recherche, Hôpital Maisonneuve-Rosemont, Faculté de Médicine, Université de Montréal, Québec, Canada (M.-O.B., F.A.L., V.P.) and Vertex Pharmaceuticals Canada Incorporated, Laval, Quebec, Canada (M.-O.B., N.C., J.L., C.B., M.-C.D., J.-F.L., L.S.-M.) Marc-Olivier.Boily@usherbrooke.ca.
authors.forename: Marc-Olivier
authors.initials: MO
authors.lastname: Boily
authors.affiliation: Service de Néphrologie et Centre de Recherche, Hôpital Maisonneuve-Rosemont, Faculté de Médicine, Université de Montréal, Québec, Canada (M.-O.B., F.A.L., V.P.) and Vertex Pharmaceuticals Canada Incorporated, Laval, Quebec, Canada (M.-O.B., N.C., J.L., C.B., M.-C.D., J.-F.L., L.S.-M.).
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chauret
authors.affiliation: Service de Néphrologie et Centre de Recherche, Hôpital Maisonneuve-Rosemont, Faculté de Médicine, Université de Montréal, Québec, Canada (M.-O.B., F.A.L., V.P.) and Vertex Pharmaceuticals Canada Incorporated, Laval, Quebec, Canada (M.-O.B., N.C., J.L., C.B., M.-C.D., J.-F.L., L.S.-M.).
authors.forename: Julie
authors.initials: J
authors.lastname: Laterreur
authors.affiliation: Service de Néphrologie et Centre de Recherche, Hôpital Maisonneuve-Rosemont, Faculté de Médicine, Université de Montréal, Québec, Canada (M.-O.B., F.A.L., V.P.) and Vertex Pharmaceuticals Canada Incorporated, Laval, Quebec, Canada (M.-O.B., N.C., J.L., C.B., M.-C.D., J.-F.L., L.S.-M.).
authors.forename: François A
authors.initials: FA
authors.lastname: Leblond
authors.affiliation: Service de Néphrologie et Centre de Recherche, Hôpital Maisonneuve-Rosemont, Faculté de Médicine, Université de Montréal, Québec, Canada (M.-O.B., F.A.L., V.P.) and Vertex Pharmaceuticals Canada Incorporated, Laval, Quebec, Canada (M.-O.B., N.C., J.L., C.B., M.-C.D., J.-F.L., L.S.-M.).
authors.forename: Chantal
authors.initials: C
authors.lastname: Boudreau
authors.affiliation: Service de Néphrologie et Centre de Recherche, Hôpital Maisonneuve-Rosemont, Faculté de Médicine, Université de Montréal, Québec, Canada (M.-O.B., F.A.L., V.P.) and Vertex Pharmaceuticals Canada Incorporated, Laval, Quebec, Canada (M.-O.B., N.C., J.L., C.B., M.-C.D., J.-F.L., L.S.-M.).
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Duquet
authors.affiliation: Service de Néphrologie et Centre de Recherche, Hôpital Maisonneuve-Rosemont, Faculté de Médicine, Université de Montréal, Québec, Canada (M.-O.B., F.A.L., V.P.) and Vertex Pharmaceuticals Canada Incorporated, Laval, Quebec, Canada (M.-O.B., N.C., J.L., C.B., M.-C.D., J.-F.L., L.S.-M.).
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Lévesque
authors.affiliation: Service de Néphrologie et Centre de Recherche, Hôpital Maisonneuve-Rosemont, Faculté de Médicine, Université de Montréal, Québec, Canada (M.-O.B., F.A.L., V.P.) and Vertex Pharmaceuticals Canada Incorporated, Laval, Quebec, Canada (M.-O.B., N.C., J.L., C.B., M.-C.D., J.-F.L., L.S.-M.).
authors.forename: Line
authors.initials: L
authors.lastname: Ste-Marie
authors.affiliation: Service de Néphrologie et Centre de Recherche, Hôpital Maisonneuve-Rosemont, Faculté de Médicine, Université de Montréal, Québec, Canada (M.-O.B., F.A.L., V.P.) and Vertex Pharmaceuticals Canada Incorporated, Laval, Quebec, Canada (M.-O.B., N.C., J.L., C.B., M.-C.D., J.-F.L., L.S.-M.).
authors.forename: Vincent
authors.initials: V
authors.lastname: Pichette
mesh_terms: D000818:Animals; D004347:Drug Interactions / Q000502:physiology; D005746:Gastric Emptying / Q000187:drug effects / Q000502:physiology; D008297:Male; D008790:Metoprolol / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014230:Triazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D014230:Triazoles; C033020:1-aminobenzotriazole; D008790:Metoprolol