title: Carrier-Mediated Prodrug Uptake to Improve the Oral Bioavailability of Polar Drugs: An Application to an Oseltamivir Analogue.
abstract: The goal of this study was to improve the intestinal mucosal cell membrane permeability of the poorly absorbed guanidino analogue of a neuraminidase inhibitor, oseltamivir carboxylate (GOC) using a carrier-mediated strategy. Valyl amino acid prodrug of GOC with isopropyl-methylene-dioxy linker (GOC-ISP-Val) was evaluated as the potential substrate for intestinal oligopeptide transporter, hPEPT1 in Xenopus laevis oocytes heterologously expressing hPEPT1, and an intestinal mouse perfusion system. The diastereomers of GOC-ISP-Val were assessed for chemical and metabolic stability. Permeability of GOC-ISP-Val was determined in Caco-2 cells and mice. Diastereomer 2 was about 2 times more stable than diastereomer 1 in simulated intestinal fluid and rapidly hydrolyzed to the parent drug in cell homogenates. The prodrug had a 9 times-enhanced apparent permeability (P(app)) in Caco-2 cells compared with the parent drug. Both diastereomer exhibited high effective permeability (P(eff)) in mice, 6.32 ± 3.12 and 5.20 ± 2.81 × 10(-5) cm/s for diastereomer 1 and 2, respectively. GOC-ISP-Val was found to be a substrate of hPEPT1. Overall, this study indicates that the prodrug, GOC-ISP-Val, seems to be a promising oral anti-influenza agent that has sufficient stability at physiologically relevant pHs before absorption, significantly improved permeability via hPEPT1 and potentially rapid activation in the intestinal cells.
authors: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109; Department of Pharmaceutical Technology, Faculty of Pharmacy, Gazi University, Ankara 06330, Turkey.
authors: Tuba
authors: T
authors: Incecayir
authors: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109.
authors: Jing
authors: J
authors: Sun
authors: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109.
authors: Yasuhiro
authors: Y
authors: Tsume
authors: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109.
authors: Hao
authors: H
authors: Xu
authors: Department of Membrane Transport and Biopharmaceutics, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, 920-1192, Japan.
authors: Tomoka
authors: T
authors: Gose
authors: Department of Membrane Transport and Biopharmaceutics, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, 920-1192, Japan.
authors: Takeo
authors: T
authors: Nakanishi
authors: Department of Membrane Transport and Biopharmaceutics, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, 920-1192, Japan.
authors: Ikumi
authors: I
authors: Tamai
authors: TSRL Inc., Ann Arbor, Michigan 48108.
authors: John
authors: J
authors: Hilfinger
authors: TSRL Inc., Ann Arbor, Michigan 48108.
authors: Elke
authors: E
authors: Lipka
authors: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109. Electronic address: glamidon@umich.edu.
authors: Gordon L
authors: GL
authors: Amidon
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000378:metabolism; D001682:Biological Availability; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology; D004337:Drug Carriers / Q000008:administration & dosage / Q000378:metabolism*; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D053139:Oseltamivir / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism*; D011355:Prodrugs / Q000008:administration & dosage / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D000998:Antiviral Agents; D004337:Drug Carriers; D011355:Prodrugs; D053139:Oseltamivir
keywords: Caco-2 cells; absorption potential; active transport; cell culture; membrane transport and transporters; peptide transporters; permeability; prodrugs