The Herb–Drug Pharmacokinetic Interaction of 5-Fluorouracil and Its Metabolite 5-Fluoro-5,6-Dihydrouracil with a Traditional Chinese Medicine in Rats

Abstract

Background: Xiang-Sha-Liu-Jun-Zi-Tang (XSLJZT) is the most common traditional formula given to colorectal and breast cancer patients in Taiwan, according to a statistical study of the National Health Insurance Research Database. 5-Fluorouracil (5-FU) is widely used as the first line of treatment for colorectal cancer. Thus, the aim of study is to investigate the pharmacokinetic interaction of XSLJZT and 5-FU. Methods: To investigate the herb–drug interaction of XSLJZT with 5-FU as well as its metabolite 5-fluoro-5,6-dihydrouracil (5-FDHU) using pharmacokinetics, a high-performance liquid chromatography (HPLC) system coupled with a photodiode array detector was developed to monitor 5-FU and 5-FDHU levels in rat blood. Rats were divided into three cohorts, one of which was administered 5-FU (100 mg/kg, iv—intravenous) alone, while the other two groups were pretreated with low and high doses of XSLJZT (600 mg/kg/day or 2400 mg/kg/day for 5 consecutive days) in combination with 5-FU. Results: The results demonstrated that 5-FU level was not significantly different between the group treated with only 5-FU and the group pretreated with a normal dose of XSLJZT (600 mg/kg/day). However, pharmacokinetic analysis revealed that pretreatment with a high dose of XSLJZT (2400 mg/kg/day) extended the residence time and increased the volume of distribution of 5-FU. No significant distinctions were found in 5-FDHU pharmacokinetic parameters at three doses of XSLJZT. Conclusions: Overall, the pharmacokinetic results confirm the safety of coadministering 5-FU with XSLJZT, and provide practical dosage information for clinical practice.

Colorectal cancer and therapy response: a focus on the main mechanisms involved

“…Severe 5-FU-associated toxicity (e.g., leukopenia, neutropenia, thrombocytopenia, anemia, neuropathy, skin rash, hand-foot syndrome, and so on) is mainly due to a partial or complete DPD deficiency ( 95 – 99 ). In particular, different rare variants in the gene encoding DPD (DPYD) have been identified as validated risk variants for drug toxicity ( 86 ).…”

Pharmacokinetic Comparisons of Multiple Triterpenic Acids from Jujubae Fructus Extract Following Oral Delivery in Normal and Acute Liver Injury Rats

“…The peak area ratio ( y ) of the analyte to the IS vs. the nominal concentration ( x , ng/mL) was used to plot the calibration curve and determine the linearity with weighted (1/ x 2 ) least square linear regression [ 34 ]. LLOQ of the method was determined based on the signal to noise ratio of 10:1 with the acceptable precision in six replicates of blank plasma (RSD ≤ 20%) [ 35 ].…”

Role of Platelet-activating factor and HO-1 in mediating the protective effect of rupatadine against 5-fluorouracil-induced hepatotoxicity in rats

“…After the introduction 5-FU as a chemotherapeutic drug, it has maintained a considerable clinical relevance. Certain tumor types, including colorectal, breast, esophageal, and head and neck tumors, are managed with 5-FU-based palliative chemotherapy Liu et al (2017). An essential restriction of 5-FU use is its toxicity on normal growing body cells of various organs and tissues Al-Asmari et al (2016).…”