title: Pegylation improves the pharmacokinetics and bioavailability of small-molecule drugs hydrolyzable by esterases: a study of phospho-Ibuprofen.
abstract: Esterase hydrolysis of drugs can accelerate their elimination, thereby limiting their efficacy. Polyethylene glycol (PEG) covalently attached to drugs (pegylation) is known to improve the efficiency of many drugs. Using as a test agent the novel phospho-ibuprofen (PI), we examined whether pegylation of PI could abrogate its hydrolytic degradation by esterases; PI, known to inhibit colon cancer growth, has a carboxylic ester hydrolyzable by carboxylesterases (CES). We covalently attached mPEG-2000 to PI (PI-PEG) and studied its stability by exposing it to cells overexpressing CES and by administering it to mice. We also evaluated PI-PEG's anticancer efficacy in human colon cancer xenografts and in Apc(min/+) mice. PI-PEG was stable in the presence of cells overexpressing CES1 or CES2, whereas PI was extensively hydrolyzed (90.2 ± 0.7%, 14.3 ± 1.1%, mean ± S.E.M.). In mice, PI was nearly completely hydrolyzed. Intravenous administration of PI-PEG resulted in significant levels in blood and in colon cancer xenografts (xenograft values in parentheses): area under the curve for 0-24 hours = 2351 (2621) (nmol/g) × h; Cmax = 1965 (886) nmol/g; Tmax = 0.08 (2) hour. The blood levels of ibuprofen, its main hydrolytic product, were minimal. Compared with controls, PI-PEG inhibited the growth of the xenografts by 74.8% (P < 0.01) and reduced intestinal tumor multiplicity in Apc(min/+) mice by 73.1% (P < 0.01), prolonging their survival (100% versus 55.1% of controls; P = 0.013). Pegylation protects PI from esterase hydrolysis and improves its pharmacokinetics. In preclinical models of colon cancer, PI-PEG is a safe and efficacious agent that merits further evaluation.
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, New York (G.M., C.C.W., Y.S., C.A.A., R.R., B.R.); and Medicon Pharmaceuticals, Inc. (P.P.C., B.R.), Stony Brook, New York.
authors.forename: George
authors.initials: G
authors.lastname: Mattheolabakis
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, New York (G.M., C.C.W., Y.S., C.A.A., R.R., B.R.); and Medicon Pharmaceuticals, Inc. (P.P.C., B.R.), Stony Brook, New York.
authors.forename: Chi C
authors.initials: CC
authors.lastname: Wong
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, New York (G.M., C.C.W., Y.S., C.A.A., R.R., B.R.); and Medicon Pharmaceuticals, Inc. (P.P.C., B.R.), Stony Brook, New York.
authors.forename: Yu
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, New York (G.M., C.C.W., Y.S., C.A.A., R.R., B.R.); and Medicon Pharmaceuticals, Inc. (P.P.C., B.R.), Stony Brook, New York.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Amella
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, New York (G.M., C.C.W., Y.S., C.A.A., R.R., B.R.); and Medicon Pharmaceuticals, Inc. (P.P.C., B.R.), Stony Brook, New York.
authors.forename: Robert
authors.initials: R
authors.lastname: Richards
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, New York (G.M., C.C.W., Y.S., C.A.A., R.R., B.R.); and Medicon Pharmaceuticals, Inc. (P.P.C., B.R.), Stony Brook, New York.
authors.forename: Panayiotis P
authors.initials: PP
authors.lastname: Constantinides
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, New York (G.M., C.C.W., Y.S., C.A.A., R.R., B.R.); and Medicon Pharmaceuticals, Inc. (P.P.C., B.R.), Stony Brook, New York basil.rigas@stonybrookmedicine.edu.
authors.forename: Basil
authors.initials: B
authors.lastname: Rigas
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002265:Carboxylic Ester Hydrolases / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy; D057809:HEK293 Cells; D006801:Humans; D006868:Hydrolysis; D007052:Ibuprofen / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use; D051379:Mice; D010755:Organophosphates / Q000009:adverse effects / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011092:Polyethylene Glycols / Q000737:chemistry*; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: C559491:2-(4-isobutylphenyl)propionic acid 4-(diethoxyphosphoryloxy)butyl ester; D000970:Antineoplastic Agents; D010755:Organophosphates; D011092:Polyethylene Glycols; C028210:monomethoxypolyethylene glycol; D002265:Carboxylic Ester Hydrolases; D007052:Ibuprofen