Preparation and in vivo evaluation of a water-soluble prodrug for 2R-γ-tocotrienol and as a two-step prodrug for 2,7,8-trimethyl-2S-(β- carboxyethyl)-6-hydroxychroman (S-γ-CEHC) in rat

Nami Akaho, Jiro Takata, Takeshi Fukushima, Kazuhisa Matsunaga, Akihiro Hattori, Ryoji Hidaka, Kosuke Fukui, Miyako Yoshida, Toshihiro Fujioka, Yoshiharu Karube, Kazuhiro Imai

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

2R-γ-Tocotrienol (γ-T3) is currently receiving attention because it has beneficial effects not observed with α-tocopherol. To achieve the effective delivery of γ-T3, we synthesized three kinds of ester derivatives of γ-T3 and evaluated their use as hydrophilic prodrugs for γ-T3 in vitro and in vivo. 2R-γ-Tocotrienyl N,N- dimethylaminoacetate hydrochloride (compound 3) was a solid compound, with high solubility and stability in water, and was converted to γ-T3 by esterases in rat and human liver. Intravenous administration of 3 in rats led to a rapid increase in the plasma, liver, heart, and kidney levels of γ-T3. The bioavailability (plasma level) after intravenous administration was 82.5 ± 13.4% and 100 ± 11.3% for 3 and γ-T3 in surfactant, respectively, and the availability in liver was 213 ± 47.6% and 100 ± 4.8% for 3 and γ-T3 in surfactant, respectively. Furthermore, the systemic availability of 2,7,8-trimethyl-2S-(β-carboxyethyl)-6- hydroxychroman (S-γ-CEHC), a metabolite of γ-T3, was 78.6% for compound 3, 47.1% for γ-T3 in surfactant, and 100% for racemic γ-CEHC. Based on these results, we identified compound 3 as the most promising water-soluble prodrug of γ-T3 and two-step prodrug of S-γ-CEHC.

Original languageEnglish
Pages (from-to)1502-1510
Number of pages9
JournalDrug Metabolism and Disposition
Volume35
Issue number9
DOIs
Publication statusPublished - 2007 Sep
Externally publishedYes

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Tocotrienols
Prodrugs
Surface-Active Agents
Liver
Rats
Intravenous Administration
Water
Availability
Plasmas
Tocopherols
Esterases
Metabolites
Solubility
Biological Availability
Esters
Derivatives
Kidney
carboxyethyl-hydroxychroman

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Preparation and in vivo evaluation of a water-soluble prodrug for 2R-γ-tocotrienol and as a two-step prodrug for 2,7,8-trimethyl-2S-(β- carboxyethyl)-6-hydroxychroman (S-γ-CEHC) in rat. / Akaho, Nami; Takata, Jiro; Fukushima, Takeshi; Matsunaga, Kazuhisa; Hattori, Akihiro; Hidaka, Ryoji; Fukui, Kosuke; Yoshida, Miyako; Fujioka, Toshihiro; Karube, Yoshiharu; Imai, Kazuhiro.

In: Drug Metabolism and Disposition, Vol. 35, No. 9, 09.2007, p. 1502-1510.

Research output: Contribution to journalArticle

Akaho, Nami ; Takata, Jiro ; Fukushima, Takeshi ; Matsunaga, Kazuhisa ; Hattori, Akihiro ; Hidaka, Ryoji ; Fukui, Kosuke ; Yoshida, Miyako ; Fujioka, Toshihiro ; Karube, Yoshiharu ; Imai, Kazuhiro. / Preparation and in vivo evaluation of a water-soluble prodrug for 2R-γ-tocotrienol and as a two-step prodrug for 2,7,8-trimethyl-2S-(β- carboxyethyl)-6-hydroxychroman (S-γ-CEHC) in rat. In: Drug Metabolism and Disposition. 2007 ; Vol. 35, No. 9. pp. 1502-1510.
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abstract = "2R-γ-Tocotrienol (γ-T3) is currently receiving attention because it has beneficial effects not observed with α-tocopherol. To achieve the effective delivery of γ-T3, we synthesized three kinds of ester derivatives of γ-T3 and evaluated their use as hydrophilic prodrugs for γ-T3 in vitro and in vivo. 2R-γ-Tocotrienyl N,N- dimethylaminoacetate hydrochloride (compound 3) was a solid compound, with high solubility and stability in water, and was converted to γ-T3 by esterases in rat and human liver. Intravenous administration of 3 in rats led to a rapid increase in the plasma, liver, heart, and kidney levels of γ-T3. The bioavailability (plasma level) after intravenous administration was 82.5 ± 13.4{\%} and 100 ± 11.3{\%} for 3 and γ-T3 in surfactant, respectively, and the availability in liver was 213 ± 47.6{\%} and 100 ± 4.8{\%} for 3 and γ-T3 in surfactant, respectively. Furthermore, the systemic availability of 2,7,8-trimethyl-2S-(β-carboxyethyl)-6- hydroxychroman (S-γ-CEHC), a metabolite of γ-T3, was 78.6{\%} for compound 3, 47.1{\%} for γ-T3 in surfactant, and 100{\%} for racemic γ-CEHC. Based on these results, we identified compound 3 as the most promising water-soluble prodrug of γ-T3 and two-step prodrug of S-γ-CEHC.",
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AU - Akaho, Nami

AU - Takata, Jiro

AU - Fukushima, Takeshi

AU - Matsunaga, Kazuhisa

AU - Hattori, Akihiro

AU - Hidaka, Ryoji

AU - Fukui, Kosuke

AU - Yoshida, Miyako

AU - Fujioka, Toshihiro

AU - Karube, Yoshiharu

AU - Imai, Kazuhiro

PY - 2007/9

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N2 - 2R-γ-Tocotrienol (γ-T3) is currently receiving attention because it has beneficial effects not observed with α-tocopherol. To achieve the effective delivery of γ-T3, we synthesized three kinds of ester derivatives of γ-T3 and evaluated their use as hydrophilic prodrugs for γ-T3 in vitro and in vivo. 2R-γ-Tocotrienyl N,N- dimethylaminoacetate hydrochloride (compound 3) was a solid compound, with high solubility and stability in water, and was converted to γ-T3 by esterases in rat and human liver. Intravenous administration of 3 in rats led to a rapid increase in the plasma, liver, heart, and kidney levels of γ-T3. The bioavailability (plasma level) after intravenous administration was 82.5 ± 13.4% and 100 ± 11.3% for 3 and γ-T3 in surfactant, respectively, and the availability in liver was 213 ± 47.6% and 100 ± 4.8% for 3 and γ-T3 in surfactant, respectively. Furthermore, the systemic availability of 2,7,8-trimethyl-2S-(β-carboxyethyl)-6- hydroxychroman (S-γ-CEHC), a metabolite of γ-T3, was 78.6% for compound 3, 47.1% for γ-T3 in surfactant, and 100% for racemic γ-CEHC. Based on these results, we identified compound 3 as the most promising water-soluble prodrug of γ-T3 and two-step prodrug of S-γ-CEHC.

AB - 2R-γ-Tocotrienol (γ-T3) is currently receiving attention because it has beneficial effects not observed with α-tocopherol. To achieve the effective delivery of γ-T3, we synthesized three kinds of ester derivatives of γ-T3 and evaluated their use as hydrophilic prodrugs for γ-T3 in vitro and in vivo. 2R-γ-Tocotrienyl N,N- dimethylaminoacetate hydrochloride (compound 3) was a solid compound, with high solubility and stability in water, and was converted to γ-T3 by esterases in rat and human liver. Intravenous administration of 3 in rats led to a rapid increase in the plasma, liver, heart, and kidney levels of γ-T3. The bioavailability (plasma level) after intravenous administration was 82.5 ± 13.4% and 100 ± 11.3% for 3 and γ-T3 in surfactant, respectively, and the availability in liver was 213 ± 47.6% and 100 ± 4.8% for 3 and γ-T3 in surfactant, respectively. Furthermore, the systemic availability of 2,7,8-trimethyl-2S-(β-carboxyethyl)-6- hydroxychroman (S-γ-CEHC), a metabolite of γ-T3, was 78.6% for compound 3, 47.1% for γ-T3 in surfactant, and 100% for racemic γ-CEHC. Based on these results, we identified compound 3 as the most promising water-soluble prodrug of γ-T3 and two-step prodrug of S-γ-CEHC.

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