title: Pharmacokinetic properties of newly synthesized retinoid X receptor agonists possessing a 6-[N-ethyl-N-(3-alkoxy-4-isopropylphenyl)amino]nicotinic acid skeleton in rats.
abstract: OBJECTIVE
  The pharmacokinetic properties of three newly synthesized retinoid X receptor (RXR) agonists were evaluated in rats to elucidate the structural factor influencing their pharmacokinetic properties.
  
  
  METHODS
  Three RXR agonists possessing a common 6-[N-ethyl-N-(3-alkoxy-4-isopropylphenyl)amino]nicotinic acid skeleton and side chain structures that are slightly different from each other were prepared as we previously reported (Takamatsu et al., ChemMedChem, 2008; 3:780-787). The plasma concentration profiles of these compounds were evaluated following the intravenous and intra-intestinal administrations. Their hepatic metabolism was characterized using rat liver microsomes.
  
  
  RESULTS
  Based on the plasma concentration profile, NEt-3IP (3-isopropoxy) was shown to have a distribution volume of 4.53 L/kg, and to be cleared from the body with an elimination half-time of 0.95 h. The bioavailability of NEt-3IP is 16.4%, whereas those of the isobutoxy analog NEt-3IB and the cyclopropylmethoxy analog NEt-3cPM are 46.5% and 22.6%, respectively. Subsequently, in the experiments using rat liver microsomes, the K(m) and V(max) values of NEt-3IP were determined as 7.85 µM and 0.48 nmol/min/mg protein, respectively. This K(m) value is nearly the same as those of NEt-3IB and NEt-3cPM, but the V(max) value is noticeably smaller. Additionally, it was revealed that the CYP family mainly metabolizing NEt-3IP is different from those metabolizing the other analogs.
  
  
  CONCLUSIONS
  Based on these findings, the pharmacokinetic properties of the compounds possessing this type of the skeleton seem to be largely influenced by a slight modification of the side chain structure.
authors.affiliation: Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
authors.forename: Akemi
authors.initials: A
authors.lastname: Ogasawara
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Murakami
authors.forename: Nobumasa
authors.initials: N
authors.lastname: Yakushiji
authors.forename: Fuminori
authors.initials: F
authors.lastname: Ohsawa
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Kusaba
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Aiba
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kurosaki
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kakuta
mesh_terms: D000818:Animals; D001682:Biological Availability; D015195:Drug Design; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D009525:Niacin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D047488:Retinoid X Receptors / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D047488:Retinoid X Receptors; D009525:Niacin