Effect of thymoquinone on pharmacokinetics of 5-fluorouracil in rats and its effect on human cell line in vitro

Abstract

Thymoquinone (TQ) is one of the components extracted from Nigella sativa seeds and has antioxidant, anti-inflammatory, and anticancer effects. We evaluated the effect of TQ on 5-fluorouracil (5-FU) pharmacokinetics (PK) in vivo and in vitro on human colorectal cancer cell line. Ten Adult male Wistar rats were assigned to two groups. TQ treated group received intraperitoneal TQ once daily for 14 consecutive days (5 mg/kg). Both groups received intraperitoneal 5-FU (50 mg/kg) on day 15 and blood samples were collected from retro-orbital plexus. The pharmacokinetics parameters were analyzed using high-performance liquid chromatography (HPLC). Moreover, various concentrations of 5-FU, TQ, and combination of 5-FU and TQ were added to the HT-29 cell line and cell viability was measured using 3- (4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide colorimetric assay. The maximum serum concentration ( Cmax), area under the curve (AUC), and time of maximum concentration ( Tmax) of 5-FU in TQ treated group were significantly increased approximately by 61, 60, and 24% compared to the control group, respectively. The combination of 5-FU with TQ (0.284 mM) showed a greater inhibitory effect on HT-29 cell growth compared to the alone 5-FU (0.027 and 0.055 mM) administration. TQ increases the AUC, Cmax, and Tmax of 5-FU and has a synergistic effect on the PK of 5-FU. Moreover, low concentration of TQ enhances the inhibitory effects of 5-FU on cell growth in colorectal cancer cell line. This synergistic effect might enhance the anticancer effects of low concentration of 5-FU, leading to drug dose reduction and reduced systemic toxicity of this chemotherapeutic agent.