In vitro metabolic biomodulation of irinotecan to increase potency and reduce dose-limiting toxicity by inhibition of SN-38 glucuronide formation

Rachel A. Crane; Emery S. Grubb; Lori U. Coward; Greg S. Gorman

doi:10.1515/dmpt-2021-0178

Article

In vitro metabolic biomodulation of irinotecan to increase potency and reduce dose-limiting toxicity by inhibition of SN-38 glucuronide formation

Rachel A. Crane , Emery S. Grubb , Lori U. Coward and Greg S. Gorman

Published/Copyright: March 7, 2022

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From the journal Drug Metabolism and Personalized Therapy Volume 37 Issue 3

Abstract

Objectives

Colorectal cancer continues to have one of the highest incidents of occurrence with a rising rate of diagnosis among people under the age of 50. Chemotherapy with irinotecan results in severe gastrointestinal dose-limiting toxicity that is caused by the glucuronidated form of the active metabolite (SN-38G). This study evaluates herbal compounds and analogs to biomodulate the metabolism of IR to decrease dose-limiting toxicity while increasing the amount of the active metabolite.

Methods

In vitro metabolism using human liver microsomes was conducted with white willow bark (WWB) extract, select specific components of WWB, and analogues to evaluate biomodulation of the IR metabolism. Samples were analyzed using liquid chromatography-tandem mass spectrometry to measure metabolites between reactions with and without herbals components.

Results

WWB showed an optimal decrease (>80%) in SN-38G and a corresponding increase in SN-38 levels (128%) at a concentration of near 200 μg/mL. Tannic acid produced a 75% decrease in SN-38G with a 130% increase in SN-38 at 10 μg/mL, whereas the treatment with beta-pentagalloyl glucose and various analogues decreased SN-38G by 70% and increased SN-38 by 20% at 10 μg/mL.

Conclusions

These results suggest naturally occurring compounds from WWB may have the potential to increase potency by increasing the conversion of IR to SN-38 and decrease dose-limiting toxicity of IR chemotherapy by reducing glucuronidation of SN-38.

Keywords: biomodulation; colorectal cancer; drug metabolism; irinotecan; prodrug; SN-38

Corresponding author: Prof. Greg S. Gorman, McWhorter School of Pharmacy, Samford University, 800 Lakeshore Drive, Birmingham, AL 35229, USA, Phone: +1 (205) 726 4452, E-mail: ggorman@samford.edu

Funding source: Pharmaceutical Sciences Research Institute McWhorter School of Pharmacy Not applicable

Award Identifier / Grant number: Not applicbale

Acknowledgments

The authors wish to thank Dr. Robert Riggs for his assistance in isolating and synthesizing the various galloyl sugar analogues.

Research funding: This study was funded by the Pharmaceutical Sciences Research Institute at the McWhorter School of Pharmacy.
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests: Authors state no conflict of interest.
Informed consent: Not applicable.
Ethical approval: Not applicable.

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Received: 2021-09-02

Revised: 2021-12-09

Accepted: 2022-01-03

Published Online: 2022-03-07

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Articles in the same Issue

https://doi.org/10.1515/dmpt-2021-0178

Keywords for this article

biomodulation; colorectal cancer; drug metabolism; irinotecan; prodrug; SN-38