title: Shedding light on minipig drug metabolism - elevated amide hydrolysis in vitro.
abstract: 1. In recent years, the minipig is increasingly used as a test species in non-clinical assessment of drug candidates. While there is good scientific evidence available concerning cytochrome P450-mediated metabolism in minipig, the knowledge of other metabolic pathways is more limited. 2. The aim of this study was to provide an understanding of when, why, and how drug metabolism in minipig differs from other species commonly used in non-clinical studies. In-house cross-species metabolite profile comparisons in hepatocytes and microsomes of 38 Roche development compounds were retrospectively analyzed to compare the metabolism among minipig, human, rat, dog, monkey, rabbit and mouse. 3. A significant contributor to the elevated metabolism observed for certain compounds in minipig was identified as amide hydrolysis. The hepatic amide hydrolysis activity in minipig was further investigated in subcellular liver fractions and a structure-activity relationship was established. When structural motifs according to the established SAR are excluded, coverage of major human metabolic pathways was shown to be higher in minipig than in dog, and only slightly lower than in cynomolgus monkey. 4. A strategy is presented for early identification of drug compounds which might not be suited to further investigation in minipig due to excessive hydrolytic metabolism.
authors.affiliation: a Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd , Basel , Switzerland and.
authors.forename: Russell
authors.initials: R
authors.lastname: Jones
authors.affiliation: a Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd , Basel , Switzerland and.
authors.forename: Michaela
authors.initials: M
authors.lastname: Marschmann
authors.affiliation: b Institut fuer Pharmazeutische Wissenschaften, Albert-Ludwigs-Universitaet Freiburg , Freiburg , Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Keller
authors.affiliation: a Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd , Basel , Switzerland and.
authors.forename: Na Hong
authors.initials: NH
authors.lastname: Qiu
authors.affiliation: a Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd , Basel , Switzerland and.
authors.forename: Stephen
authors.initials: S
authors.lastname: Fowler
authors.affiliation: a Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd , Basel , Switzerland and.
authors.forename: Thomas
authors.initials: T
authors.lastname: Singer
authors.affiliation: a Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd , Basel , Switzerland and.
authors.forename: Franz
authors.initials: F
authors.lastname: Schuler
authors.affiliation: a Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd , Basel , Switzerland and.
authors.forename: Christoph
authors.initials: C
authors.lastname: Funk
authors.affiliation: a Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd , Basel , Switzerland and.
authors.forename: Simone
authors.initials: S
authors.lastname: Schadt
mesh_terms: D000577:Amides / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D043182:Carboxylesterase / Q000378:metabolism; D000068579:Celecoxib / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D008099:Liver / Q000378:metabolism; D055442:Metabolome; D008862:Microsomes, Liver / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D013045:Species Specificity; D013329:Structure-Activity Relationship; D013347:Subcellular Fractions / Q000378:metabolism; D013552:Swine; D013556:Swine, Miniature
chemical_list: D000577:Amides; D004364:Pharmaceutical Preparations; D043182:Carboxylesterase; D000068579:Celecoxib
keywords: Amide hydrolysis; biotransformation; drug metabolism; esterase; in vitro; metabolite; minipig; species differences