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

Fingerprint

Retinoid X Receptors
Pharmacokinetics
Niacin
Skeleton
Rats
Liver Microsomes
Liver
Plasmas
Metabolism
Biological Availability
alkoxyl radical
Proteins
Experiments

Keywords

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

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmacology
  • Organic Chemistry

Cite this

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

In: Drug Development and Industrial Pharmacy, Vol. 37, No. 9, 09.2011, p. 1060-1067.

Research output: Contribution to journalArticle

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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. 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.",
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T1 - 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

AU - Ogasawara, Akemi

AU - Murakami, Yoshiki

AU - Yakushiji, Nobumasa

AU - Ohsawa, Fuminori

AU - Kusaba, Jun Ichi

AU - Aiba, Tetsuya

AU - Kurosaki, Yuji

AU - Kakuta, Hiroki

PY - 2011/9

Y1 - 2011/9

N2 - 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.

AB - 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.

KW - Bioavailability

KW - Disposition

KW - Drug design

KW - Elimination

KW - Hepatic metabolism

KW - Pharmacokinetics

KW - Retinoid X receptor

KW - Structureproperty relationship

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