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Combination of <scp>l</scp>-Carnitine with Lipophilic Linkage-Donating Gemcitabine Derivatives as Intestinal Novel Organic Cation Transporter 2-Targeting Oral Prodrugs
- Source :
- Journal of Medicinal Chemistry. 60:2552-2561
- Publication Year :
- 2017
- Publisher :
- American Chemical Society (ACS), 2017.
-
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.
- Subjects :
- 0301 basic medicine
Antimetabolites, Antineoplastic
Organic Cation Transport Proteins
02 engineering and technology
Absorption (skin)
Pharmacology
SLC22A5
Deoxycytidine
Mice
03 medical and health sciences
Carnitine
Drug Discovery
medicine
Animals
Humans
Prodrugs
Tissue Distribution
Solute Carrier Family 22 Member 5
biology
Chemistry
Metabolism
Prodrug
021001 nanoscience & nanotechnology
Gemcitabine
Bioavailability
Molecular Docking Simulation
HEK293 Cells
030104 developmental biology
Biochemistry
Caco-2
biology.protein
Molecular Medicine
Caco-2 Cells
0210 nano-technology
medicine.drug
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 60
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....921f0ab77ec2309e2335b00a0c540b63