# Mechanistic and Pharmacokinetic Studies of Classical Chinese Formula Xiao Chai Hu Tang Against Irinotecan-Induced Gut Toxicities

> **NIH NIH R01** · UNIVERSITY OF HOUSTON · 2021 · $196,895

## Abstract

Abstract
Irinotecan, a prodrug of SN-38, is used to treat many types of metastatic and drug-resistant cancers, and often
represents the therapy of the last resort. Unfortunately, a large percentage (up to 40%) of these patients will
experience serious (Grade 2) and severe (Grade 3-4) delayed-onset diarrhea (SDOD), which really downgrade
patient’s quality of life. SDOD may lead to prolonged hospitalization and even death in some instances. The
long-term goal of our research is to develop experimental therapeutics and/or nutritional supplemental approach
to reduce SDOD, so patients can sustain their chemotherapy. Our recent studies have shown that inactivation
of intestinal UDP-glucuronosyltransferases (UGTs) by SN-38 is a new mechanism by which SN-38 causes
SDOD, and that a Traditional Chinese Medicine, Xiao-Chai-Hu-Tang (XCHT), could attenuate the inactivation of
intestinal UGTs in mice. Therefore, the central hypothesis of this current proposal is Therefore, we hypothesize
that XCHT will prevent or reduce irinotecan-induced SDOD by attenuating the decline in UGT activities, reducing
gut SN-38 exposure, and promoting the recovery of gut UGT activities. We plan to test this hypothesis using four
Specific Aims: (1) perform phytochemical, biopharmaceutical and pharmacokinetic characterization of XCHT to
enable quality control, systemic and intestinal drug exposure determinations, and to provide bioanalytical
methods and pharmacokinetic parameters needed for a clinical study and PK/PD modeling; (2) validate plasma
raloxifene-4′-glucuronide levels as a probe to changes in intestinal Ugt/UGT activity; (3) Perform mouse “co-
trial” studies to support human mechanistic trials and to determine the mechanisms of action of XCHT against
irinotecan-induced SDOD using both in vitro and in vivo models; and (4) Conduct a mechanistic clinical trial using
a randomized double-blind design with a safety “Run-In” to determine if XCHT can attenuate human intestinal
UGT decrease and reduce incidence of Grade 3 or higher diarrhea caused by irinotecan chemotherapy. Aside
from these primary outcomes, we will also determine if levels of Ral-4’-G, a probe of intestinal UGT activities is
(negatively) correlated with systemic levels of inflammatory cytokines. Success gained through this research will
provide a new mechanism by which we can target to treat SDOD caused by irinotecan chemotherapy.

## Key facts

- **NIH application ID:** 10262912
- **Project number:** 5R01CA246209-02
- **Recipient organization:** UNIVERSITY OF HOUSTON
- **Principal Investigator:** MING HU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $196,895
- **Award type:** 5
- **Project period:** 2020-09-11 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10262912

## Citation

> US National Institutes of Health, RePORTER application 10262912, Mechanistic and Pharmacokinetic Studies of Classical Chinese Formula Xiao Chai Hu Tang Against Irinotecan-Induced Gut Toxicities (5R01CA246209-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10262912. Licensed CC0.

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