Pharmacokinetics and biodistribution of topical phosphosulindac and its metabolites in mice and a mouse model for chemotherapy-induced peripheral neuropathy

Article Sidebar

PDF
Published Jul 31, 2025
DOI: https://doi.org/10.18103/mra.v13i7.6792

Downloads

Download data is not yet available.

Submit your own article

Register as an author to reserve your spot in the next issue of the Medical Research Archives.

Author Registration

Join the Society

The European Society of Medicine is more than a professional association. We are a community. Our members work in countries across the globe, yet are united by a common goal: to promote health and health equity, around the world.

Join Europe’s leading medical society and discover the many advantages of membership, including free article publication.

Membership

Main Article Content

Ishan Amin Khwaja
Department of Preventive Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
Jonathan Souferian
Department of Preventive Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
Fatima B. Khwaja
Department of Preventive Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
Andrew Loiacono
Department of Preventive Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA. 2 Medicon Pharmaceuticals, Inc, Setauket, NY 11733, USA.
Cameron Takmil
Department of Preventive Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA. 2 Medicon Pharmaceuticals, Inc, Setauket, NY 11733, USA.
Vivian Zhu
Department of Preventive Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA. 2 Medicon Pharmaceuticals, Inc, Setauket, NY 11733, USA.
Owen Dong
Department of Preventive Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA. 2 Medicon Pharmaceuticals, Inc, Setauket, NY 11733, USA.
Jennifer Zeng
Department of Preventive Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
Sean Hatzidakis
Department of Preventive Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
Atahan Yetimoglu
Department of Preventive Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
Ishan Deen Khwaja
Department of Preventive Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
Emanuel Mamakas
Department of Preventive MedicineMedicon Pharmaceuticals, Inc, Setauket, NY 11733, USA., Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
Ernest Natke
Department of Ophthalmology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
Robert Honkanen
Department of Ophthalmology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
Liqun Huang
Department of Preventive Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.; Medicon Pharmaceuticals, Inc, Setauket, NY 11733, USA.
Basil Rigas
Department of Preventive Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.; Medicon Pharmaceuticals, Inc, Setauket, NY 11733, USA.

Abstract

Background: Our purpose was to determine the pharmacokinetics and biodistribution of phosphosulindac and its metabolites when applied to mouse skin. Phosphosulindac differs from sulindac by adding a diethyl-phospho-butane moiety, which enhances efficacy and safety. In preclinical studies, phosphosulindac has anti-cancer and anti-inflammatory properties and prevents and reverses chemotherapy-induced peripheral neuropathy


Methods: Phosphosulindac gel was applied topically to the hind paws of normal mice and those with chemotherapy-induced peripheral neuropathy. Samples from the paw skin, paw muscle, leg muscle, sciatic nerve, dorsal root ganglia and blood, obtained at various time points, were assayed using HPLC for phosphosulindac, and its metabolites (sulindac, sulindac sulfide, sulindac sulfone).


Results: Topically applied phosphosulindac was detected in paw skin, paw and adjacent leg muscles where it reached its Tmax in 0.5 h. Smaller amounts of phosphosulindac were detected in sciatic nerve (Tmax = 3 h) and dorsal root ganglia (at 24 h). Phosphosulindac was not found in blood. Absorption of phosphosulindac was concentration-dependent and pH-sensitive. Its metabolites were detected in paw skin, vicinal muscles, sciatic nerve, and blood but not in dorsal root ganglia. Topically applied equimolar sulindac was detected in paw skin and muscle and in smaller amounts in leg muscle and sciatic nerve.


Conclusion: Phosphosulindac is absorbed through the paw skin and transported from paw and leg muscle to the sciatic nerve and dorsal root ganglia, its target tissues in normal and chemotherapy-induced peripheral neuropathy mice. In contrast, sulindac is transported through the same tissues as well as by the circulation.

Keywords: Topical application, Preclinical pharmacokinetics, Phosphosulindac, OXT-328, Sulindac, Modified NSAIDs, CIPN

Article Details

How to Cite
KHWAJA, Ishan Amin et al. Pharmacokinetics and biodistribution of topical phosphosulindac and its metabolites in mice and a mouse model for chemotherapy-induced peripheral neuropathy. Medical Research Archives, [S.l.], v. 13, n. 7, july 2025. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/6792>. Date accessed: 06 dec. 2025. doi: https://doi.org/10.18103/mra.v13i7.6792.
ABNT APA BibTeX CBE EndNote - EndNote format (Macintosh & Windows) MLA ProCite - RIS format (Macintosh & Windows) RefWorks Reference Manager - RIS format (Windows only) Turabian
Issue
Vol 13 No 7 (2025): Vol.13, Issue 7, July 2025
Section
Research Articles

The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.

 

References

1. Mackenzie GG, Sun Y, Huang L, et al. Phospho-sulindac (OXT-328), a novel sulindac derivative, is safe and effective in colon cancer prevention in mice. Gastroenterology. 2010;139(4):1320-32. doi: 10.1053/j.gastro.2010.06.044.
2. Murray OT, Wong CC, Vrankova K, Rigas B. Phospho-sulindac inhibits pancreatic cancer growth: NFATc1 as a drug resistance candidate. Int J Oncol. 2014;44(2):521-9. doi: 10.3892/ijo.2013.2190.
3. Cheng KW, Wong CC, Alston N, et al. Aerosol administration of phospho-sulindac inhibits lung tumorigenesis. Mol Cancer Ther. 2013;12(8):1417-28. doi: 10.1158/1535-7163.MCT-13-0006-T.
4. Zhu R, Cheng KW, Mackenzie G, et al. Phospho-sulindac (OXT-328) inhibits the growth of human lung cancer xenografts in mice: enhanced efficacy and mitochondria targeting by its formulation in solid lipid nanoparticles. Pharm Res. 2012;29(11):3090-101. doi: 10.1007/s11095-012-0801-x.
5. Cheng KW, Mattheolabakis G, Wong CC, et al. Topical phospho-sulindac (OXT-328) is effective in the treatment of non-melanoma skin cancer. Int J Oncol. 2012;41(4):1199-203. doi: 10.3892/ijo.2012.1577.
6. Mattheolabakis G, Mackenzie GG, Huang L, Ouyang N, Cheng KW, Rigas B. Topically applied phospho-sulindac hydrogel is efficacious and safe in the treatment of experimental arthritis in rats. Pharm Res. 2013;30(6):1471-82. doi: 10.1007/s11095-012-0953-8.
7. Basu A, Yang JY, Tsirukis VE, et al. Phosphosulindac (OXT-328) prevents and reverses chemotherapy induced peripheral neuropathy in mice. Front. Neurosci. 2024;17 doi: 10.3389/fnins.2023. 1240372.
8. Colvin LA. Chemotherapy-induced peripheral neuropathy: where are we now? Pain. 2019;160 Suppl 1:S1-S10. doi: 10.1097/j.pain.0000000000001540.
9. Wong CC, Cheng KW, Papayannis I, et al. Phospho-NSAIDs have enhanced efficacy in mice lacking plasma carboxylesterase: implications for their clinical pharmacology. Pharm Res. 2015;32(5):1663-75. doi: 10.1007/s11095-014-1565-2.
10. Wong CC, Cheng KW, Xie G, et al. Carboxylesterases 1 and 2 hydrolyze phospho-nonsteroidal anti-inflammatory drugs: relevance to their pharmacological activity. J Pharm Exp Ther. 2012;340(2):422-32. doi: 10.1124/jpet.111.188508.
11. Xie G, Nie T, Mackenzie GG, et al. The metabolism and pharmacokineticsof phospho-sulindac (OXT-328) and the effect of difluoromethylornithine. Br J Pharmacol. 2012;165(7):2152-66. doi: 10.1111/j.1476-5381.2011.01705.x.
12. Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol. 2010;8(6):e1000412. doi: 10.1371/ journal.pbio.1000412.
13. Wen Z, Muratomi N, Huang W, et al. The ocular pharmacokinetics and biodistribution of phospho-sulindac (OXT-328) formulated in nanoparticles: Enhanced and targeted tissue drug delivery. Int J Pharm. 2019;557:273-9. doi: 10.1016/j.ijpharm. 2018.12.057.
14. Currie GL, Angel-Scott HN, Colvin L, et al. Animal models of chemotherapy-induced peripheral neuropathy: A machine-assisted systematic review and meta-analysis. PLoS Biol. 2019;17(5):e3000243. doi: 10.1371/journal.pbio.3000243.
15. Eldridge S, Guo L, Hamre J III. A comparative review of chemotherapy-induced peripheral neuropathy in in vivo and in vitro models. Toxicol Pathol. 2020;48(1):190-201. doi: 10.1177/0192623319 861937.
16. Carozzi VA, Canta A, Oggioni N, et al. Neurophysiological and neuropathological characterization of new murine models of chemotherapy-induced chronic peripheral neuropathies. Exp Neurol. 2010;226(2):301-9. doi: 10.1016/j.expneurol.2010.09.004.
17. Toma W, Kyte SL, Bagdas D, et al. Effects of paclitaxel on the development of neuropathy and affective behaviors in the mouse. Neuropharmacol. 2017;117:305-15. doi: 10.1016/j.neuropharm.2017.02.020.
18. Hab Y, Smith MT. Pathobiology of cancer chemotherapy-induced peripheral neuropathy (CIPN). Front Pharmacol. 2013;4:1-16. doi: 10.3389/fphar.2013.00156.
19. Ferly J, Colombet M, Soerjomataram I, et al. Cancer statistics for the year 2020: An overview. Int J Cancer. 2021;149:778-789. doi: 10.1002/ijc.33588.
20. Shapiro CL. Cancer survivorship. N Engl J Med. 2018;379(25):2438-2450. doi: 10.1056/NEJMra 1712502.
21. Flatters SJL, Dougherty PM, Colvin LA. Clinical and preclinical perspectives on chemotherapy-induced peripheral neuropathy (CIPN): a narrative review. BJA. 2017;119(4):737-49. doi: 10.1093/bja/ aex229.
22. Chen X, Gan Y, Au NPB, Ma CHE. Current understanding of the molecular mechanisms of chemotherapy-induced peripheral neuropathy. Front Mol Neurosci. 2024;17:1345811. doi: 10.3389/ fnmol.2024.1345811.
23. Loprinzi CL, Lacchetti C, Bleeker J, et al. Prevention and managerment of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: ASCO guideline update. J Clin Oncol. 2020;38(28):3325-3348. doi: 10.1200/JCO.20. 01399.
24. Maihofner C, Diel I, Tesch H, Quandel T, Baron R. Chemotherapy-induced peripheral neuropathy (CIPN): current therapies and topical treatment option with high-concentration capsaicin. Support Care Cancer. 2021;29:4223-4238. doi: 10.1007/ s00520-021-06042-x.
25. Desforges AD, Hebert CM, Spence A, et al. Treatment and diagnosis of chemotherapy-induced peripheral neuropathy: An update. Biomed Pharmacother. 2022;147:112671. doi: 10.1016/j.biopha.2022. 112671.
26. Xie G, Wong CC, Cheng KW, Huang L, Constantinides PP, Rigas B. Regioselective oxidation of phospho-NSAIDs by human cytochrome P450 and flavin monooxygenase isoforms: implications for their pharmacokinetic properties and safety. Br J Pharmacol. 2012;167(1):222-32. doi: 10.1111/ j.1476-5381.2012.01982.x.

27. Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013;138(1):103-41. doi:10.1016/j.pharmthera.2012.12.007.