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.

Keywords: 5-fluoro-5,6-dihydrouracil (5-FDHU); 5-fluorouracil (5-FU); HPLC–UV; Xiang-Sha-Liu-Jun-Zi-Tang (XSLJZT); herb–drug interaction; pharmacokinetic; traditional Chinese medicine (TCM).

Figure 1

Metabolic pathway of 5-FU. 5-FU: 5-fluorouracil; 5-FDHU: 5-fluoro-5,6-dihydrouracil; FUPA: 5-fluoro-ureido-propionic; FBAL: α-fluoro-β-alanine; DPD: dihydropyrimidine dehydrogenase.

Figure 2

HPLC chromatograms of (A) blank plasma samples; (B) blank plasma samples spiked with 5-FU (10 µg/mL), 5-FDHU (10 µg/mL), and internal standard (20 µg/mL); and (C) blood sample containing 5-FU collected at 30 min after 5-FU (100 mg/kg, iv) administration alone. Peak 1: 5-FDHU with a retention time of 5.8 min. Peak 2: 5-FU with a retention time of 6.8 min. Peak 3: Internal standard amoxicillin with a retention time of 14.2 min.

Figure 3

Mean plasma concentration-time curve of 5-FU in rat blood after 5-FU administration (100 mg/kg, iv) alone (●) and 5-FU with a dose of XSLJZT (600 mg/kg/day, po for 5 consecutive days) (○) and XSLJZT (2400 mg/kg/day, po for 5 consecutive days) (▼). po: by mouth; iv: intravenous.

Figure 4

Mean plasma concentration–time curve of 5-FDHU in rat blood after 5-FU administration (100 mg/kg, iv) alone (●), 5-FU with dose of XSLJZT (600 mg/kg/day, po for 5 consecutive days) (○) and XSLJZT (2400 mg/kg/day, po for 5 consecutive days) (▼). po: by mouth; iv: intravenous.