title: Interspecies comparison of hepatic metabolism of six newly synthesized retinoid X receptor agonistic compounds possessing a 6-[N-ethyl-N-(alkoxyisopropylphenyl)amino]nicotinic acid skeleton in rat and human liver microsomes.
abstract: OBJECTIVE
  The hepatic metabolism of six compounds newly synthesized as retinoid X receptor agonists was characterized in rat and human liver microsomes to examine the relationship between their hepatic metabolism profiles and side chain structures, considering the interspecies difference.
  
  
  METHODS
  The compounds used have a 6-[N-ethyl-N-(3-alkoxy-4-isopropylphenyl)amino]nicotinic or 6-[N-ethyl-N-(4-alkoxy-3-isopropylphenyl)amino]nicotinic acid skeleton, in which the isopropoxy, isobutoxy or cyclopropylmethoxy group is employed for the alkoxy group. These compounds were incubated with the microsomes, and their Michaelis--Menten parameters were determined. The incubation study was also performed with various cytochrome P450 (CYP) inhibitors to examine their susceptibilities to the inhibitors. In addition, a molecular docking simulation was conducted to assess the compound's spatial configuration with the CYP isoform when necessary.
  
  
  RESULTS
  The Michaelis--Menten parameters determined are comparable between rats and humans for the compounds having 3-isobutoxy, 4-isobutoxy, 4-isopropoxy and 4-cyclopropylmethoxy groups. However, it was indicated that all compounds except that having the 3-isobutoxy group are metabolized in a different manner between rats and humans. That is, the extent of the contribution of each CYP isozyme is different between those two species. A molecular docking simulation showed that the spatial configuration of the compound to be associated with CYP2D6 markedly changes depending on whether the isobutoxy group is situated at the 3- or 4-position.
  
  
  CONCLUSIONS
  A slight difference in the side chain structures markedly alters the compound's metabolic profile, which amplifies the interspecies difference regarding the profile, increasing the difficulty in characterizing the profile in humans with the structural-property relationship and interspecies extrapolation.
authors.affiliation: Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University , Tsushima-Naka, Okayama , Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Murakami
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Shimizu
authors.forename: Akemi
authors.initials: A
authors.lastname: Ogasawara
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ueshima
authors.forename: Mariko
authors.initials: M
authors.lastname: Nakayama
authors.forename: Kohei
authors.initials: K
authors.lastname: Kawata
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kakuta
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Aiba
mesh_terms: D000818:Animals; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D062105:Molecular Docking Simulation / Q000379:methods; D009525:Niacin / Q000494:pharmacology*; D051381:Rats; D047488:Retinoid X Receptors / Q000819:agonists* / Q000378:metabolism
chemical_list: D047488:Retinoid X Receptors; D009525:Niacin; D003577:Cytochrome P-450 Enzyme System; D019389:Cytochrome P-450 CYP2D6
keywords: Cytochrome P450; drug design; hepatic metabolism; interspecies difference; retinoid X receptor agonist; structure-property relationship