title: Preparation and in vivo evaluation of a water-soluble prodrug for 2R-gamma-tocotrienol and as a two-step prodrug for 2,7,8-trimethyl-2S-(beta-carboxyethyl)-6-hydroxychroman (S-gamma-CEHC) in rat.
abstract: 2R-gamma-Tocotrienol (gamma-T3) is currently receiving attention because it has beneficial effects not observed with alpha-tocopherol. To achieve the effective delivery of gamma-T3, we synthesized three kinds of ester derivatives of gamma-T3 and evaluated their use as hydrophilic prodrugs for gamma-T3 in vitro and in vivo. 2R-gamma-Tocotrienyl N,N-dimethylamino-acetate hydrochloride (compound 3) was a solid compound, with high solubility and stability in water, and was converted to gamma-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 gamma-T3. The bioavailability (plasma level) after intravenous administration was 82.5 +/- 13.4% and 100 +/- 11.3% for 3 and gamma-T3 in surfactant, respectively, and the availability in liver was 213 +/- 47.6% and 100 +/- 4.8% for 3 and gamma-T3 in surfactant, respectively. Furthermore, the systemic availability of 2,7,8-trimethyl-2S-(beta-carboxyethyl)-6-hydroxychroman (S-gamma-CEHC), a metabolite of gamma-T3, was 78.6% for compound 3, 47.1% for gamma-T3 in surfactant, and 100% for racemic gamma-CEHC. Based on these results, we identified compound 3 as the most promising water-soluble prodrug of gamma-T3 and two-step prodrug of S-gamma-CEHC.
authors.affiliation: Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma, Johnan-ku, Fukuoka 814-0180, Japan.
authors.forename: Nami
authors.initials: N
authors.lastname: Akaho
authors.forename: Jiro
authors.initials: J
authors.lastname: Takata
authors.forename: Takeshi
authors.initials: T
authors.lastname: Fukushima
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Matsunaga
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hattori
authors.forename: Ryoji
authors.initials: R
authors.lastname: Hidaka
authors.forename: Kosuke
authors.initials: K
authors.lastname: Fukui
authors.forename: Miyako
authors.initials: M
authors.lastname: Yoshida
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Fujioka
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Karube
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Imai
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D002839:Chromans / Q000008:administration & dosage / Q000302:isolation & purification / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004952:Esters / Q000138:chemical synthesis / Q000494:pharmacology; D005079:Excipients; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000378:metabolism; D000073878:Palm Oil; D019999:Pharmaceutical Solutions; D010830:Physostigmine / Q000494:pharmacology; D010938:Plant Oils / Q000737:chemistry; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D011422:Propionates / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet; D013501:Surface-Active Agents / Q000494:pharmacology; D014018:Tissue Distribution; D014810:Vitamin E / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000494:pharmacology
chemical_list: D002839:Chromans; D004952:Esters; D005079:Excipients; D019999:Pharmaceutical Solutions; D010938:Plant Oils; D011355:Prodrugs; D011422:Propionates; D013501:Surface-Active Agents; D014810:Vitamin E; C107690:2,7,8-trimethyl-2-(beta-carboxyethyl)-6-hydroxychroman; C013649:plastochromanol 8; D000073878:Palm Oil; D010830:Physostigmine