title: Combination of l-Carnitine with Lipophilic Linkage-Donating Gemcitabine Derivatives as Intestinal Novel Organic Cation Transporter 2-Targeting Oral Prodrugs.
abstract: Novel organic cation transporter 2 (OCTN2, SLC22A5) is responsible for the uptake of carnitine through the intestine and, therefore, might be a promising molecular target for designing oral prodrugs. Poor permeability and rapid metabolism have greatly restricted the oral absorption of gemcitabine. We here describe the design of intestinal OCTN2-targeting prodrugs of gemcitabine by covalent coupling of l-carnitine to its N4-amino group via different lipophilic linkages. Because of the high OCTN2 affinity, the hexane diacid-linked prodrug demonstrated significantly improved stability (3-fold), cellular permeability (15-fold), and oral bioavailability (5-fold), while causing no toxicity as compared to gemcitabine. In addition, OCTN2-targeting prodrugs can simultaneously improve the permeability, solubility, and metabolic stability of gemcitabine. In summary, we present the first evidence that OCTN2 can act as a new molecular target for oral prodrug delivery and, importantly, the linkage carbon chain length is a key factor in modifying the affinity of the substrate for OCTN2.
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University , Wenhua Road, Shenyang 110016, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University , Wenhua Road, Shenyang 110016, China.
authors.forename: Hongxiang
authors.initials: H
authors.lastname: Chen
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University , Wenhua Road, Shenyang 110016, China.
authors.forename: Dongyang
authors.initials: D
authors.lastname: Zhao
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University , Wenhua Road, Shenyang 110016, China.
authors.forename: Dawei
authors.initials: D
authors.lastname: Ding
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University , Wenhua Road, Shenyang 110016, China.
authors.forename: Mengchi
authors.initials: M
authors.lastname: Sun
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University , Wenhua Road, Shenyang 110016, China.
authors.forename: Longfa
authors.initials: L
authors.lastname: Kou
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University , Wenhua Road, Shenyang 110016, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Luo
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University , Wenhua Road, Shenyang 110016, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research , Tianjin, China.
authors.forename: Xiulin
authors.initials: X
authors.lastname: Yi
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University , Wenhua Road, Shenyang 110016, China.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Dong
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education , Shenyang, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University , Wenhua Road, Shenyang 110016, China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Liu
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University , Wenhua Road, Shenyang 110016, China.
authors.forename: Zhonggui
authors.initials: Z
authors.lastname: He
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University , Wenhua Road, Shenyang 110016, China.|Municipal Key Laboratory of Biopharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University , Shenyang, China.
authors.forename: Jin
authors.identifier: 0000-0001-7385-9017
authors.initials: J
authors.lastname: Sun
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D018938:Caco-2 Cells; D002331:Carnitine / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D011355:Prodrugs / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D000074058:Solute Carrier Family 22 Member 5; D014018:Tissue Distribution; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D027701:Organic Cation Transport Proteins; D011355:Prodrugs; C492020:SLC22A5 protein, human; D000074058:Solute Carrier Family 22 Member 5; D003841:Deoxycytidine; D002331:Carnitine; D000093542:Gemcitabine