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

Akemi Ogasawara, Yoshiki Murakami, Nobumasa Yakushiji, Fuminori Ohsawa, Jun Ichi Kusaba, Tetsuya Aiba, Yuji Kurosaki, Hiroki Kakuta

Research output: Contribution to journalArticle

2 Citations (Scopus)

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. Material and 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. Conclusion: 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.

Original languageEnglish
Pages (from-to)1060-1067
Number of pages8
JournalDrug Development and Industrial Pharmacy
Volume37
Issue number9
DOIs
Publication statusPublished - Sep 2011

Keywords

  • Bioavailability
  • Disposition
  • Drug design
  • Elimination
  • Hepatic metabolism
  • Pharmacokinetics
  • Retinoid X receptor
  • Structureproperty relationship

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry

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