Esterase hydrolysis of drugs can accelerate their elimination, thereby limiting their efficacy. Covalently attaching polyethylene glycol (PEG) on drugs (pegylation) is known to improve the efficiency of many drugs. Using as a test agent the novel phospho-ibuprofen (PI), the authors examined whether pegylation of PI (PI-PEG) could abrogate its hydrolytic degradation by esterases. PI-PEG was stable in the presence of cells overexpressing carboxylesterases, while PI was extensively hydrolyzed. In mice, PI was nearly completely hydrolyzed, but intravenous administration of PI-PEG resulted in significant levels in blood and in colon cancer xenografts. Compared with controls, PI-PEG inhibited the growth of the xenografts by 74.8% and reduced intestinal tumor multiplicity in Apcmin/+ mice by 73.1%, prolonging their survival (100% versus 55.1% of controls). These results demonstrate that pegylation protects PI from esterase hydrolysis and improves its pharmacokinetics and efficacy in preclinical models of colon cancer.
See article at J Pharmacol Exp Ther 2014, 351:61–66.
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