Regioselective oxidation of phospho‐NSAIDs by human cytochrome P450 and flavin monooxygenase isoforms: implications for their pharmacokinetic properties and safety

Xie, Gang; Wong, Chi Chun; Cheng, Ka‐Wing; Huang, Liqun; Constantinides, Panayiotis P.; Rigas, Basil

doi:10.1111/j.1476-5381.2012.01982.x

Cited by 26 publications

(13 citation statements)

References 27 publications

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“…Although not fully understood, the safety of PS is partly attributed to its unique pharmacokinetic properties: the blood AUC 0-24 h of PS is around 40% of that produced by an equimolar amount of sulindac while in the stomach, the main site of NSAID toxicity, PS is mainly intact and its two gastrotoxic metabolites, sulindac and sulindac sulfide, are present in miniscule amounts (39). PS's more rapid detoxification by cytochrome P450s and flavin monooxygenases seems to contribute to its safety (40). …”

Section: Chemopreventive Efficacymentioning

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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Section: Chemopreventive Efficacymentioning

confidence: 99%

NSAIDs and Colorectal Cancer Control: Promise and Challenges

Tsioulias

Rigas

2015

Curr Pharmacol Rep

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“…In gastroduodenal wall of mice, 71% of phospho‐sulindac was found to be intact, which explained the gastrosparing characters of it. Xie et al further studied the metabolism of phospho‐ibuprofen (MDC‐917) and phospho‐sulindac (OXT‐328) by major human CYPs and flavin monooxygenases (FMOs) . Oxidation of phospho‐ibuprofen was catalyzed by CYP isoforms CYP1A2, 2C19, 2D6, and 3A4, but not of ibuprofen.…”

Section: Development Of Various Nsaids and Their Derivativesmentioning

confidence: 99%

Recent Developments in Chimeric NSAIDs as Safer Anti‐Inflammatory Agents

Kumar

Sharma

2014

Medicinal Research Reviews

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NSAIDs are among the most widely prescribed medications across the world, but the gastrointestinal (GI) toxicity still remains the biggest problem and the challenge for current NSAIDs-based therapeutics. The development of selective COX-2 inhibitors was driven by the assumption that selective inhibition of COX-2 would reduce the GI side effects. However, the initial enthusiasm for selective COX-2 inhibitors has faded away due to the emergence of serious side effects associated with the long-term use of these NSAIDs. In the recent years, a number of novel approaches to develop gastrosparing NSAIDs have been explored with the promising results. This review deals with such approaches and strategies that have been employed in the last two decades and are being used currently in the design and development of safer NSAIDs.

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“…174 Evidence suggests that FMO is also involved in the metabolism of certain drugs. [175][176][177][178] The main role of the FMO pathway appears to be as a scavenger system with a low specificity, carrying out oxidation of thousands of substrates, most notably nucleophilic amines and sulphides. 174 One of these substrates is trimethylamine (TMA), which has a fish like odour, becoming ammoniacal at higher concentrations.…”

Section: Trimethylaminuriamentioning

confidence: 99%

Dimethylsulphidemia: the significance of dimethyl sulphide in extra-oral, blood borne halitosis

Harvey-Woodworth¹

2013

Br Dent J

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Halitosis is a symptom and not a diagnosis. Rather, the topic represents a spectrum of disorders, including intra-oral, otorhinolaryngological, metabolic, systemic, pulmonary, psychological and neurological conditions. Halitosis may be the third most common trigger for patients to seek dental care and can cause significant impact on patient quality of life. About 10% of all genuine halitosis cases are attributed to extra-oral processes. Some authorities have reported that the nasal cavity and the oropharynx are the most common sites of origin of extra-oral halitosis. However, recent evidence appears to suggest that blood borne halitosis may be the most common subtype of extra-oral halitosis. Tangerman and Winkel report that dimethyl sulphide was the main volatile implicated in extra-oral blood borne halitosis. They proposed a hitherto unknown metabolic condition by way of explanation for this finding, resulting in systemic presence of dimethyl sulphide in blood and alveolar breath. This paper reviews the knowledge base regarding the behaviour of dimethyl sulphide in physiological systems and those disorders in which blood borne halitosis secondary to dimethylsulphidemia is thought to have an aetiopathological role.

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Regioselective oxidation of phospho‐NSAIDs by human cytochrome P450 and flavin monooxygenase isoforms: implications for their pharmacokinetic properties and safety

Cited by 26 publications

References 27 publications

NSAIDs and Colorectal Cancer Control: Promise and Challenges

NSAIDs and Colorectal Cancer Control: Promise and Challenges

Recent Developments in Chimeric NSAIDs as Safer Anti‐Inflammatory Agents

Dimethylsulphidemia: the significance of dimethyl sulphide in extra-oral, blood borne halitosis

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