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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number15760
JournalScientific reports
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2019

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Therapeutic Uses
Metabolic Networks and Pathways
Nucleosides
Adenosine
Oral Administration
Blood Circulation
Drug Discovery
cordycepin
Macrophages
Pharmaceutical Preparations
3'-deoxyinosine

All Science Journal Classification (ASJC) codes

  • General

Cite this

Lee, J. B., Radhi, M., Cipolla, E., Gandhi, R. D., Sarmad, S., Zgair, A., ... Gershkovich, P. (2019). A novel nucleoside rescue metabolic pathway may be responsible for therapeutic effect of orally administered cordycepin. Scientific reports, 9(1), [15760]. https://doi.org/10.1038/s41598-019-52254-x
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 A. ; Barrett, David A. ; Kagan, Leonid ; Fischer, Peter M. ; de Moor, Cornelia H. ; Gershkovich, Pavel. / A novel nucleoside rescue metabolic pathway may be responsible for therapeutic effect of orally administered cordycepin. In: Scientific reports. 2019 ; Vol. 9, No. 1.
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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.",
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Lee, JB, Radhi, M, Cipolla, E, Gandhi, RD, Sarmad, S, Zgair, A, Kim, TH, Feng, W, Qin, C, Adrower, C, Ortori, CA, Barrett, DA, Kagan, L, Fischer, PM, de Moor, CH & Gershkovich, P 2019, 'A novel nucleoside rescue metabolic pathway may be responsible for therapeutic effect of orally administered cordycepin', Scientific reports, vol. 9, no. 1, 15760. https://doi.org/10.1038/s41598-019-52254-x

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 A.; Barrett, David A.; Kagan, Leonid; Fischer, Peter M.; de Moor, Cornelia H.; Gershkovich, Pavel.

In: Scientific reports, Vol. 9, No. 1, 15760, 01.12.2019.

Research output: Contribution to journalArticle

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T1 - A novel nucleoside rescue metabolic pathway may be responsible for therapeutic effect of orally administered cordycepin

AU - Lee, Jong Bong

AU - Radhi, Masar

AU - Cipolla, Elena

AU - Gandhi, Raj D.

AU - Sarmad, Sarir

AU - Zgair, Atheer

AU - Kim, Tae Hwan

AU - Feng, Wanshan

AU - Qin, Chaolong

AU - Adrower, Cecilia

AU - Ortori, Catherine A.

AU - Barrett, David A.

AU - Kagan, Leonid

AU - Fischer, Peter M.

AU - de Moor, Cornelia H.

AU - Gershkovich, Pavel

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

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