title: Enhanced absorption and growth inhibition with amino acid monoester prodrugs of floxuridine by targeting hPEPT1 transporters.
abstract: A series of amino acid monoester prodrugs of floxuridine was synthesized and evaluated for the improvement of oral bioavailability and the feasibility of target drug delivery via oligopeptide transporters. All floxuridine 5'-amino acid monoester prodrugs exhibited PEPT1 affinity, with inhibition coefficients of Gly-Sar uptake (IC50) ranging from 0.7 - 2.3 mM in Caco-2 and 2.0 - 4.8 mM in AsPC-1 cells, while that of floxuridine was 7.3 mM and 6.3 mM, respectively. Caco-2 membrane permeabilities of floxuridine prodrugs (1.01 - 5.31 x 10(-6 )cm/sec) and floxuridine (0.48 x 10(-6 )cm/sec) were much higher than that of 5-FU (0.038 x 10(-6) cm/sec). MDCK cells stably transfected with the human oligopeptide transporter PEPT1 (MDCK/hPEPT1) exhibited enhanced cell growth inhibition in the presence of the prodrugs. This prodrug strategy offers great potential, not only for increased drug absorption but also for improved tumor selectivity and drug efficacy.
authors: Department of Pharmaceutical Science, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109-1065, USA. ytsume@umich.edu
authors: Yasuhiro
authors: Y
authors: Tsume
authors: Balvinder S
authors: BS
authors: Vig
authors: Jing
authors: J
authors: Sun
authors: Christopher P
authors: CP
authors: Landowski
authors: John M
authors: JM
authors: Hilfinger
authors: Chandrasekharan
authors: C
authors: Ramachandran
authors: Gordon L
authors: GL
authors: Amidon
mesh_terms: D000042:Absorption / Q000187:drug effects; D000596:Amino Acids / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000138:chemical synthesis / Q000494:pharmacology*; D018938:Caco-2 Cells; D049109:Cell Proliferation / Q000187:drug effects*; D004285:Dogs; D016503:Drug Delivery Systems; D004952:Esters; D005467:Floxuridine / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006131:Growth Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D000074011:Peptide Transporter 1; D011355:Prodrugs / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology*; D027981:Symporters / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D000964:Antimetabolites, Antineoplastic; D004952:Esters; D006131:Growth Inhibitors; D000074011:Peptide Transporter 1; D011355:Prodrugs; C082186:SLC15A1 protein, human; D027981:Symporters; D005467:Floxuridine