ArticleBritish journal of pharmacology2012
Regioselective oxidation of phospho-NSAIDs by human cytochrome P450 and flavin monooxygenase isoforms: implications for their pharmacokinetic properties and safety.
Article in British journal of pharmacology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
10 citing papers in PubMed, 28 citations in OpenAlex.
- Spontaneously hypertensive rats exhibit increased liver flavin monooxygenase expression and elevated plasma TMAO levels compared to normotensive and Ang II-dependent hypertensive rats.Frontiers in physiology · 2024Article
- Roles of selected non-P450 human oxidoreductase enzymes in protective and toxic effects of chemicals: review and compilation of reactions.Archives of toxicology · 2022Review
- A critical review of cannabis in medicine and dentistry: A look back and the path forward.Clinical and experimental dental research · 2022Review
- Antifibrogenic Influence ofOxidative medicine and cellular longevity · 2018Article
- NSAIDs and Colorectal Cancer Control: Promise and Challenges.Current pharmacology reports · 2015Article
- Hepatocyte Growth Factor Mediates the Antifibrogenic Action of Ocimum bacilicum Essential Oil against CCl4-Induced Liver Fibrosis in Rats.Molecules (Basel, Switzerland) · 2015Article
- The evolving role of nonsteroidal anti-inflammatory drugs in colon cancer prevention: a cause for optimism.The Journal of pharmacology and experimental therapeutics · 2015Review
- The in vitro metabolism of phospho-sulindac amide, a novel potential anticancer agent.Biochemical pharmacology · 2014Article
- Comparative bioavailability and tolerability of single and multiple doses of 2 diclofenac sodium sustained-release tablet formulations in fasting, healthy chinese male volunteers.Current therapeutic research, clinical and experimental · 2013Article
- Comparative in vitro metabolism of phospho-tyrosol-indomethacin by mice, rats and humans.Biochemical pharmacology · 2013Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
background and purposePhospho-ibuprofen (MDC-917) and phospho-sulindac (OXT-328) are highly effective in cancer and arthritis treatment in preclinical models. Here, we investigated their metabolism by major human cytochrome P450s (CYPs) and flavin monooxygenases (FMOs). EXPERIMENTAL APPROACH: The CYP/FMO-catalysed metabolism of phospho-ibuprofen and phospho-sulindac was studied by using in silico prediction modelling and a direct experimental approach. KEY
resultsThe CYP isoforms catalyse the oxidation of non-steroidal anti-inflammatory drugs (NSAIDs) and phospho-NSAIDs, with distinct activity and regioselectivity. CYP1A2, 2C19, 2D6 and 3A4 oxidize phospho-ibuprofen, but not ibuprofen; whereas CYP2C9 oxidizes ibuprofen, but not phospho-ibuprofen. All CYPs tested oxidize phospho-sulindac, but not sulindac. Among the five CYPs evaluated, CYP3A4 and 2D6 are the most active in the oxidation of phospho-ibuprofen and phospho-sulindac respectively. FMOs oxidized phospho-sulindac and sulindac, but not phospho-ibuprofen or ibuprofen. FMOs were more active towards phospho-sulindac than sulindac, indicating that phospho-sulindac is a preferred substrate of FMOs. The susceptibility of phospho-NSAIDs to CYP/FMO-mediated metabolism was also reflected in their rapid oxidation by human and mouse liver microsomes, which contain a full complement of CYPs and FMOs. Compared with conventional NSAIDs, the higher activity of CYPs towards phospho-ibuprofen and phospho-sulindac may be due to their greater lipophilicity, a key parameter for CYP binding. CONCLUSIONS AND IMPLICATIONS: CYPs and FMOs play an important role in the metabolism of phospho-NSAIDs, resulting in differential pharmacokinetic profiles between phospho-NSAIDs and NSAIDs in vivo. The consequently more rapid detoxification of phospho-NSAIDs is likely to contribute to their greater safety.
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