Pegylation Improves the Pharmacokinetics and Bioavailability of Small-Molecule Drugs Hydrolyzable by Esterases: A Study of Phospho-Ibuprofen

Mattheolabakis, George; Wong, Chi Chun; Sun, Yu; Amella, C. A.; Richards, Robert J.; Constantinides, Panayiotis P.; Rigas, Basil

doi:10.1124/jpet.114.217208

Cited by 25 publications

(18 citation statements)

References 14 publications

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“…Although PEGylation of small molecules with relatively long PEG chains (>2 kDa) has previously been reported to improve PK, it was unexpected to discover that conjugation with only two ethylene glycol repeating units was sufficient to increase systemic exposure 73 . The prolonged plasma half-life of (OEG 2 ) 2 -IP4 compared to IP6, observed in healthy animals, is likely due to the enhanced metabolic stability of (OEG 2 ) 2 -IP4.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of vascular calcification by inositol phosphates derivatized with ethylene glycol oligomers

et al. 2020

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Myo-inositol hexakisphosphate (IP6) is a natural product known to inhibit vascular calcification (VC), but with limited potency and low plasma exposure following bolus administration. Here we report the design of a series of inositol phosphate analogs as crystallization inhibitors, among which 4,6-di-O-(methoxy-diethyleneglycol)-myo-inositol-1,2,3,5-tetrakis (phosphate), (OEG 2) 2-IP4, displays increased in vitro activity, as well as more favorable pharmacokinetic and safety profiles than IP6 after subcutaneous injection. (OEG 2) 2-IP4 potently stabilizes calciprotein particle (CPP) growth, consistently demonstrates low micromolar activity in different in vitro models of VC (i.e., human serum, primary cell cultures, and tissue explants), and largely abolishes the development of VC in rodent models, while not causing toxicity related to serum calcium chelation. The data suggest a mechanism of action independent of the etiology of VC, whereby (OEG 2) 2-IP4 disrupts the nucleation and growth of pathological calcification.

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Section: Resultsmentioning

confidence: 99%

Inhibition of vascular calcification by inositol phosphates derivatized with ethylene glycol oligomers

et al. 2020

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“…In particular, their carboxylic moiety is often esterified to a dialcohol spacer moiety; the second – OH of the spacer is linked to a diethylphosphate moiety, which enhances cellular uptake (14). Recently, one of the phospho-NSAIDs was pegylated to improve its pharmacokinetics and bioavailability (15). …”

Section: Nsaids Old and Newmentioning

confidence: 99%

NSAIDs and Colorectal Cancer Control: Promise and Challenges

Tsioulias

Rigas

2015

Curr Pharmacol Rep

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The chemoprevention of colorectal cancer (CRC) is a realistic option given the low acceptance and cost of screening colonoscopy. NSAIDs, currently not recommended for CRC prevention, are the most promising agents. Here, we review relevant work and assess the chemopreventive potential of NSAIDs. The chemopreventive efficacy of NSAIDs is established by epidemiological and interventional studies as well as analyses of cardiovascular-prevention randomized clinical trials. The modest chemopreventive efficacy of NSAIDs is compounded by their significant toxicity that can be cumulative. Efforts to overcome these limitations include the use of drug combinations; the emphasis on the early stages of colon carcinogenesis such as aberrant crypt foci, which may require shorter periods of drug administration; and the development of several families of chemically modified NSAIDs such as derivatives of sulindac, nitro-NSAIDs and phospho-NSAIDs, with some of them appearing to have higher safety and efficacy than conventional NSAIDs and thus to be better candidate agents. The successful development of NSAIDs as chemopreventive agents will likely require a combination of the following: identification of subjects at high risk and/or those most likely to benefit from chemoprevention; optimization of the timing, dose and duration of administration of the chemopreventive agent; novel NSAID derivatives and/or combinations of agents; and agents that may prevent other diseases in addition to CRC. Ultimately, the clinical implementation of NSAIDs for the prevention of CRC will depend on a strategy that drastically shifts the currently unacceptable risk/benefit ratio in favor of chemoprevention.

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“…PS's more rapid detoxification by cytochrome P450s and flavin monooxygenases seems to contribute to its safety . An interesting phospho-NSAID is the recently reported pegylated derivative of phospho-ibuprofen (Mattheolabakis et al, 2014). Polyethylene glycol was covalently attached to phospho-ibuprofen, known to inhibit colon cancer growth , to abrogate its hydrolytic degradation by esterases; many phospho-NSAIDs are carboxylic esters hydrolyzable by carboxylesterases .…”

Section: Evolving Role Of Nsaids In Colon Cancer Preventionmentioning

confidence: 99%

The Evolving Role of Nonsteroidal Anti-Inflammatory Drugs in Colon Cancer Prevention: A Cause for Optimism

Rigas

Tsioulias

2015

J Pharmacol Exp Ther

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Colorectal cancer (CRC) is a serious yet preventable disease. The low acceptance and cost of colonoscopy as a screening method for CRC make chemoprevention an important option. Nonsteroidal anti-inflammatory drugs (NSAIDs), not currently recommended for CRC prevention, have the potential to evolve into the agents of choice for this indication. Here, we discuss the promise and challenge of NSAIDs for this chemopreventive application. Multiple epidemiologic studies, randomized clinical trials (RCTs) of sporadic colorectal polyp recurrence, RCTs in patients with hereditary colorectal cancer syndromes, and pooled analyses of cardiovascular-prevention RCTs linked to cancer outcomes have firmly established the ability of conventional NSAIDs to prevent CRC. NSAIDs, however, are seriously limited by their toxicity, which can become cumulative with their long-term administration for chemoprevention, whereas drug interactions in vulnerable elderly patients compound their safety. Newer, chemically modified NSAIDs offer the hope of enhanced efficacy and safety. Recent work also indicates that targeting earlier stages of colorectal carcinogenesis, such as the lower complexity aberrant crypt foci, is a promising approach that may only require relatively short use of chemopreventive agents. Drug combination approaches exemplified by sulindac plus difluoromethylornithine appear very efficacious. Identification of those at risk or most likely to benefit from a given intervention using predictive biomarkers may usher in personalized chemoprevention. Agents that offer simultaneous chemoprevention of diseases in addition to CRC, e.g., cardiovascular and/or neurodegenerative diseases, may have a much greater potential for a broad clinical application.

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Pegylation Improves the Pharmacokinetics and Bioavailability of Small-Molecule Drugs Hydrolyzable by Esterases: A Study of Phospho-Ibuprofen

Cited by 25 publications

References 14 publications

Inhibition of vascular calcification by inositol phosphates derivatized with ethylene glycol oligomers

Inhibition of vascular calcification by inositol phosphates derivatized with ethylene glycol oligomers

NSAIDs and Colorectal Cancer Control: Promise and Challenges

The Evolving Role of Nonsteroidal Anti-Inflammatory Drugs in Colon Cancer Prevention: A Cause for Optimism

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