A novel nucleoside rescue metabolic pathway may be responsible for therapeutic effect of orally administered cordycepin

Lee, Jong Bong; Radhi, Masar; Cipolla, Elena; Gandhi, Raj D.; Sarmad, Sarir; Zgair, Atheer; Kim, Tae Hwan; Feng, Wanshan; Qin, Chaolong; Adrower, Cecilia; Ortori, Catherine; Barrett, David A; Kagan, Leonid; Fischer, Peter M.; De Moor, Cornelia H.; Gershkovich, Pavel

Abstract

Although adenosine and its analogues have been assessed in the past as potential drug candidates due to the important role of adenosine in physiology, only little is known about their absorption following oral administration. In this work, we have studied the oral absorption and disposition pathways of cordycepin, an adenosine analogue. In vitro biopharmaceutical properties and in vivo oral absorption and disposition of cordycepin were assessed in rats. Despite the fact that numerous studies showed efficacy following oral dosing of cordycepin, we found that intact cordycepin was not absorbed following oral administration to rats. However, 3′-deoxyinosine, a metabolite of cordycepin previously considered to be inactive, was absorbed into the systemic blood circulation. Further investigation was performed to study the conversion of 3′-deoxyinosine to cordycepin 5′-triphosphate in vitro using macrophage-like RAW264.7 cells. It demonstrated that cordycepin 5′-triphosphate, the active metabolite of cordycepin, can be formed not only from cordycepin, but also from 3′-deoxyinosine. The novel nucleoside rescue metabolic pathway proposed in this study could be responsible for therapeutic effects of adenosine and other analogues of adenosine following oral administration. These findings may have importance in understanding the physiology and pathophysiology associated with adenosine, as well as drug discovery and development utilising adenosine analogues.

Citation

Lee, J. B., Radhi, M., Cipolla, E., Gandhi, R. D., Sarmad, S., Zgair, A., Kim, T. H., Feng, W., Qin, C., Adrower, C., Ortori, C., Barrett, D. A., Kagan, L., Fischer, P. M., De Moor, C. H., & Gershkovich, P. (2019). A novel nucleoside rescue metabolic pathway may be responsible for therapeutic effect of orally administered cordycepin. Scientific Reports, 9, Article 15760. https://doi.org/10.1038/s41598-019-52254-x

• Journal Article Type: Article
• Acceptance Date: Oct 12, 2019
• Online Publication Date: Oct 31, 2019
• Publication Date: 2019-12
• Deposit Date: Oct 15, 2019
• Publicly Available Date: Nov 1, 2019
• Journal: Scientific Reports
• Electronic ISSN: 2045-2322
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 9
• Article Number: 15760
• DOI: https://doi.org/10.1038/s41598-019-52254-x
• Keywords: Adenosine; 3’-deoxyadenosine; 3’-deoxyinosine; Cordycepin triphosphate;Pharmacokinetics; Metabolite
• Public URL: https://nottingham-repository.worktribe.com/output/2841558
• Publisher URL: https://www.nature.com/articles/s41598-019-52254-x
• Additional Information: Received: 8 May 2019; Accepted: 12 October 2019; First Online: 31 October 2019; : The authors declare no competing interests.
• Contract Date: Nov 1, 2019