Herb-Drug Pharmacokinetic Interaction of a Traditional Chinese Medicine Jia-Wei-Xiao-Yao-San with 5-Fluorouracil in the Blood and Brain of Rat Using Microdialysis

Abstract

According to a survey from the National Health Insurance Research Database (NHIRD), Jia-Wei-Xiao-Yao-San (JWXYS) is the most popular Chinese medicine for cancer patients in Taiwan. 5-Fluorouracil (5-FU) is a general anticancer drug for the chemotherapy. To investigate the herb-drug interaction of JWXYS on pharmacokinetics of 5-FU, a microdialysis technique coupled with a high-performance liquid chromatography system was used to monitor 5-FU in rat blood and brain. Rats were divided into four parallel groups, one of which was treated with 5-FU (100 mg/kg, i.v.) alone and the remaining three groups were pretreated with a different dose of JWXYS (600, 1200, or 2400 mg/kg/day for 5 consecutive days) followed by a combination with 5-FU. This study demonstrates that 5-FU with JWXYS (600 mg/kg/day or 1200 mg/kg/day) has no significant effect on the pharmacokinetics of 5-FU in the blood and brain. However, JWXYS (2400 mg/kg/day) coadministered with 5-FU extends the elimination half-life and increases the volume of distribution of 5-FU in the blood. The elimination half-life of 5-FU in the brain for the pretreatment group with 2400 mg/kg/day of JWXYS is significantly longer than that for the group treated with 5-FU alone and also reduces the clearance. This study provides practical dosage information for clinical practice and proves the safety of 5-FU coadministered with JWXYS.

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

“…Heggie’s study describing the characteristics of 5-FU in intravenously treated patients reported that the half-life and residence time of 5-FU are much shorter than that of its metabolite, 5-FDHU [ 38 ]. No significant correlations in 5-FDHU pharmacokinetic parameters were found between the three dosages levels of XSLJZT used in this study, in agreement with Chiang’s studies [ 10 ]. In conclusion, the present study provides not only a detailed comparison of the herbal–drug pharmacokinetic interaction of 5-FU and its main metabolite 5-FDHU with XSLJZT in rat blood, but warns that 5-FU-associated toxicity must be considered when coupled with high doses of XSLJZT.…”

“…Our findings are supported by our previous study of 5-FU, in which we found no significant differences resulting from concurrent use with the traditional medicines XSLJZT and JWXYS [ 10 ]. Although the results for 5-FU and 5-FDHU did not significantly differ between the 5-FU alone cohort and the group pretreated with a daily dose of XSLJZT (600 mg/kg/day) for five consecutive days, the time-concentration profile indicates that pretreatment with a high-dose of XSLJZT (2400 mg/kg/day) can extend the residence time of 5-FU in blood (that of 5-FDHU is rarely prolonged).…”

“…In addition to the prolonged duration of 5-FU circulation, another issue is that DPD is the initial rate-limiting enzyme in pyrimidine catabolism, which could induce the degradation of 5-FU into its major catabolite 5-FDHU [ 36 ]. Moreover, the relationship between the blood concentration of 5-FU and 5-FDHU are correlated with the toxicity of 5-FU injection in cancer patients [ 10 , 37 ]. Heggie’s study describing the characteristics of 5-FU in intravenously treated patients reported that the half-life and residence time of 5-FU are much shorter than that of its metabolite, 5-FDHU [ 38 ].…”

“…In analytical chemistry, high-performance liquid chromatography (HPLC) is a technique applied to separate, identify, and quantify each component in a sample. Our previous studies have discussed the methods for quantification of 5-FU by using HPLC, but still, few methods could measure 5-FDHU simultaneously [ 10 ]. To date, there was no method using HPLC to monitor 5-FU and its metabolite 5-FDHU, with a traditional Chinese medicine, in a single quantitative assay.…”

Integrated Chinese Herbal Medicine and Western Medicine on the Survival in Patients with Colorectal Cancer: A Retrospective Study of Medical Records

“…e therapeutic effect of this herb could be through the alleviation of psychosomatic stress as a result of colon cancer treatment [20]. With reasonable doses, Jia Wei Xiao Yao San is safe and does not interact with 5-FU in conventional treatment [21].…”