title: Co-delivery of honokiol, a constituent of Magnolia species, in a self-microemulsifying drug delivery system for improved oral transport of lipophilic sirolimus.
abstract: Sirolimus is recognized as a P-glycoprotein (P-gp) substrate with poor water-solubility. To improve its solubility and bioabsorption, self-microemulsifying drug delivery systems (SMEDDS) containing a novel P-gp inhibitor, honokiol, were prepared. The aim of this work was to evaluate the enhanced transport of sirolimus SMEDDS as well as the roles of honokiol. In situ single-pass intestinal perfusion and in vitro human colon adenocarcinoma (Caco-2) cell models were applied to study the effects of honokiol within SMEDDS on the transport of sirolimus. The results indicated that a combination of honokiol with sirolimus in SMEDDS did not significantly alter the particle size, polydispersity index and release of drugs. In addition, the absorption rate constant (Ka) as well as the effective permeability coefficients (Peff) of sirolimus in situ intestinal absorption, and the apparent permeability coefficients (Papp) of sirolimus in caco-2 cells were significantly enhanced by cremophor EL-based SMEDDS with honokiol as compared with those of SMEDDS without honokiol. Rhodamine123 uptake rate in caco-2 cells and in vitro cytotoxicity of sirolimus were enhanced by honokiol in SMEDDS indicating a substantial P-gp inhibition of honokiol. In conclusion, coadministration of honokiol with poor soluble P-gp substrate in SMEDDS, could serve as a favorable approach for oral delivery.
authors.affiliation: a Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College , Beijing , China and.
authors.forename: Weiming
authors.initials: W
authors.lastname: Ding
authors.affiliation: a Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College , Beijing , China and.
authors.forename: Xucheng
authors.initials: X
authors.lastname: Hou
authors.affiliation: b Department of Pharmaceutics , School of Pharmaceutical Sciences, Peking University , Beijing , P.R. China.
authors.forename: Shuangchen
authors.initials: S
authors.lastname: Cong
authors.affiliation: b Department of Pharmaceutics , School of Pharmaceutical Sciences, Peking University , Beijing , P.R. China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: b Department of Pharmaceutics , School of Pharmaceutical Sciences, Peking University , Beijing , P.R. China.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Chen
authors.affiliation: b Department of Pharmaceutics , School of Pharmaceutical Sciences, Peking University , Beijing , P.R. China.
authors.forename: Jiongxi
authors.initials: J
authors.lastname: Lei
authors.affiliation: b Department of Pharmaceutics , School of Pharmaceutical Sciences, Peking University , Beijing , P.R. China.
authors.forename: Yansha
authors.initials: Y
authors.lastname: Meng
authors.affiliation: b Department of Pharmaceutics , School of Pharmaceutical Sciences, Peking University , Beijing , P.R. China.
authors.forename: Xinru
authors.initials: X
authors.lastname: Li
authors.affiliation: a Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College , Beijing , China and.
authors.forename: Guiling
authors.initials: G
authors.lastname: Li
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry* / Q000378:metabolism; D000284:Administration, Oral; D001682:Biological Availability; D001713:Biphenyl Compounds / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D018938:Caco-2 Cells; D016503:Drug Delivery Systems / Q000379:methods*; D004655:Emulsions; D006801:Humans; D007408:Intestinal Absorption; D017705:Lignans / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D031566:Magnolia / Q000737:chemistry*; D010539:Permeability; D020123:Sirolimus / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D012995:Solubility; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001713:Biphenyl Compounds; D004655:Emulsions; D017705:Lignans; D020123:Sirolimus; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols
keywords: Honokiol; self-microemulsifying drug delivery system; sirolimus; transport; uptake