title: Effect of deuteration on metabolism and clearance of Nerispirdine (HP184) and AVE5638.
abstract: Replacing hydrogen with deuterium as a means of altering ADME properties of drug molecules has recently enjoyed a renaissance, such that at least two deuterated chemical entities are currently in clinical development. Although most research in this area aims to increase the metabolic stability, and hence half-life of the active species, experience has shown that prediction of the in vivo behaviour of deuterated molecules is difficult and depends on multiple factors including the complexity of the metabolic scheme, the enzymes involved and hence the mechanism of the rate-determining step in the biotransformation. In an effort to elucidate some of these factors we examined the metabolic behaviour of two molecules from the Sanofi portfolio in a range of in vitro and in vivo systems. Although some key metabolic reactions of the acetylcholine release stimulator HP184 4 were slowed in vitro and in vivo when deuterium was present at the sites of metabolism, this did not translate to an increase in overall metabolic stability. By contrast, the tryptase inhibitor AVE5638 13 was much more metabolically stable in vitro in its deuterated form than when unlabelled. These results indicate that it could be of value to concentrate efforts in this area to molecules which are metabolised by a major pathway that involves enzymes of the amine oxidase family or other low-capacity enzyme families.
authors.affiliation: Sanofi R&D, DSAR-DD, 1, Avenue Pierre Brossolette, 91385 Chilly-Mazarin, France. Electronic address: joseph.schofield@sanofi.com.
authors.forename: Joseph
authors.initials: J
authors.lastname: Schofield
authors.affiliation: Sanofi R&D, DSAR-DD, Industriepark Höchst, 65926 Frankfurt am Main, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Derdau
authors.affiliation: Sanofi R&D, DSAR-DD, Industriepark Höchst, 65926 Frankfurt am Main, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Atzrodt
authors.affiliation: Sanofi R&D, DSAR-DD, 55 Corporate Drive, Bridgewater, NJ 08807, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Zane
authors.affiliation: Sanofi R&D, DSAR-DD, 55 Corporate Drive, Bridgewater, NJ 08807, USA.
authors.forename: Zuyu
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Sanofi R&D, DSAR-DD, 55 Corporate Drive, Bridgewater, NJ 08807, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: van Horn
authors.affiliation: Sanofi R&D, DSAR-DD, 13, Quai Jules Guesde, 94400 Vitry-sur-Seine, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Czepczor
authors.affiliation: Sanofi R&D, DSAR-DD, 13, Quai Jules Guesde, 94400 Vitry-sur-Seine, France.
authors.forename: Axelle
authors.initials: A
authors.lastname: Stoltz
authors.affiliation: Sanofi R&D, DSAR-DD, 1, Avenue Pierre Brossolette, 91385 Chilly-Mazarin, France.
authors.forename: Magalie
authors.initials: M
authors.lastname: Pardon
mesh_terms: D000818:Animals; D001711:Biotransformation; D002460:Cell Line; D018679:Cholinergic Agonists / Q000097:blood* / Q000493:pharmacokinetics; D003903:Deuterium; D004355:Drug Stability; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D006859:Hydrogen; D007211:Indoles / Q000097:blood* / Q000493:pharmacokinetics; D008297:Male; D008995:Monoamine Oxidase / Q000378:metabolism; D011725:Pyridines / Q000097:blood* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014361:Trypsin Inhibitors / Q000097:blood* / Q000493:pharmacokinetics
chemical_list: D018679:Cholinergic Agonists; D007211:Indoles; D011725:Pyridines; D014361:Trypsin Inhibitors; D006859:Hydrogen; D003903:Deuterium; D008995:Monoamine Oxidase; C101289:nerispirdine
keywords: Cytochrome P450; Deuterium; H/D exchange; Isotope effects; Metabolism; Monoamine oxidase; SSAO; Stable isotopes