The metabolism and pharmacokinetics of phospho‐sulindac (OXT‐328) and the effect of difluoromethylornithine

@article{Xie2012TheMA,
  title={The metabolism and pharmacokinetics of phospho‐sulindac (OXT‐328) and the effect of difluoromethylornithine},
  author={Gang Xie and Ting Nie and G G Mackenzie and Y Sun and L. Huang and Nengtai Ouyang and Ninche Alston and C. Zhu and Onika T. Murray and Panayiotis Constantinides and Levy Kopelovich and Basil Rigas},
  journal={British Journal of Pharmacology},
  year={2012},
  volume={165}
}
  • G. Xie, T. Nie, B. Rigas
  • Published 1 April 2012
  • Medicine, Biology, Chemistry
  • British Journal of Pharmacology
BACKGROUND AND PURPOSE Phospho‐sulindac (PS; OXT‐328) prevents colon cancer in mice, especially when combined with difluoromethylornithine (DFMO). Here, we explored its metabolism and pharmacokinetics. 
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References

SHOWING 1-10 OF 51 REFERENCES
Phospho-Sulindac (OXT-328) Combined with Difluoromethylornithine Prevents Colon Cancer in Mice
TLDR
P-S/DFMO is an efficacious drug combination for colon cancer prevention and also show the safety of P-S, which may overcome the limiting side effects of conventional sulindac.
Phospho-sulindac (OXT-328), a novel sulindac derivative, is safe and effective in colon cancer prevention in mice.
BACKGROUND & AIMS Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective cancer chemopreventive agents. However, chronic administration of NSAIDs is associated with significant side effects,
Mitochondrial uncoupling by the sulindac metabolite, sulindac sulfide.
TLDR
Sulindac sulfide caused mitochondrial uncoupling, released preaccumulated Ca2+ from the organelle, and decreased Hep-G2 cell viability in apparent association with cell ATP depletion resulting from mitochondrial uncOUpling-associated membrane potential dissipation.
The novel phospho‐non‐steroidal anti‐inflammatory drugs, OXT‐328, MDC‐22 and MDC‐917, inhibit adjuvant‐induced arthritis in rats
TLDR
Three novel modified NSAIDs are evaluated for the anti‐inflammatory efficacy and safety in rheumatoid arthritis: phospho‐aspirin,ospho‐ibuprofen and phospho-sulindac.
The Role of Cyclooxygenase Inhibition in the Antineoplastic Effects of Nonsteroidal Antiinflammatory Drugs (Nsaids)
According to WHO statistics, in 1996 875,000 new cases of colorectal cancer were diagnosed and 495,000 deaths were attributed to it worldwide ([1][1]). It is the third most common cause of cancer
Sulindac sulfide suppresses 5-lipoxygenase at clinically relevant concentrations
TLDR
Mechanistic analysis demonstrated that SSi directly suppresses 5-LO with an IC50 of 20 μM, which may provide a novel molecular basis to explain the COX-independent pharmacological effects of sulindac under therapy.
Phospho-Ibuprofen (MDC-917) Is a Novel Agent against Colon Cancer: Efficacy, Metabolism, and Pharmacokinetics in Mouse Models
  • G. Xie, Yu Sun, B. Rigas
  • Biology, Chemistry
    Journal of Pharmacology and Experimental Therapeutics
  • 2011
TLDR
The results provide a pharmacological basis to explain, at least in part, the anticancer efficacy and safety of this promising compound and indicate that PI merits further evaluation as an anticancer agent.
In Vitro Metabolism of Nitric Oxide-Donating Aspirin: The Effect of Positional Isomerism
TLDR
The three positional isomers of NO-ASA differ in their metabolism and these differences correlate with their differential effects on cancer cell growth, underscoring the importance of positional isomerism in modulating drug effects.
Effect of Carboxylesterase Inhibition on the Anti-Tumour Effects of Irinotecan
TLDR
A direct correlation was found between the dose of administered BNPP and the growth rate of the tumour, demonstrating that the anti-tumour effects of CPT-11 were related to the CE concentration.
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