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

Abstract

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