The Promotive Effects of Antioxidative Apigenin on the Bioavailability of Paclitaxel for Oral Delivery in Rats

Abstract

-This study was to investigate the effect of apigenin on the bioavailability of paclitaxel after oral and intravenous administration in rats. The effect of apigenin on P-glycoprotein (P-gp), cytochrome P450 (CYP)3A4 activity was evaluated. The pharmacokinetic parameters of paclitaxel were determined in rats after oral (40 mg/kg) or intravenous (5 mg/kg) administration of paclitaxel with apigenin (0.4, 2 and 8 mg/kg) to rats. Apigenin inhibited CYP3A4 activity with 50% inhibition concentration (IC50) of 1.8 μM. In addition, apigenin significantly inhibited P-gp activity. Compared to the control group, apigenin significantly increased the area under the plasma concentration-time curve (AUC, p＜0.05 by 2 mg/kg, 59.0% higher; p＜0.01 by 8 mg/kg, 87% higher) of oral paclitaxel. Apigenin also significantly (p＜0.05 by 2 mg/kg, 37.2% higher; p＜0.01 by 8 mg/kg, 59.3% higher) increased the peak plasma concentration (C max ) of oral paclitaxel. Apigenin significantly increased the terminal half-life (t1/2, p＜0.05 by 8 mg/kg, 34.5%) of oral paclitaxel. Consequently, the absolute bioavailability (A.B.) of paclitaxel was significantly (p＜0.05 by 2 mg/kg, p＜0.01 by 8 mg/kg) increased by apigenin compared to that in the control group, and the relative bioavailability (R.B.) of oral paclitaxel was increased by 1.14-to 1.87-fold. The pharmacokinetics of intravenous paclitaxel were not affected by the concurrent use of apigenin in contrast to the oral administration of paclitaxel. Accordingly, the enhanced oral bioavailability by apigenin may be mainly due to increased intestinal absorption caused via P-gp inhibition by apigenin rather than to reduced renal and hepatic elimination of paclitaxel. The increase in the oral bioavailability might be mainly attributed to enhanced absorption in the gastrointestinal tract via the inhibition of P-gp and reduced first-pass metabolism of paclitaxel via the inhibition of the CYP3A subfamily in the small intestine and/or in the liver by apigenin. It appears that the development of oral paclitaxel preparations as a combination therapy is possible, which will be more convenient than the i.v. dosage form.

Inhibitory Effect of Acacetin, Apigenin, Chrysin and Pinocembrin on Human Cytochrome P450 3A4

“…[22] Apigenin has been shown to inhibit P450 3A4 in an assay using 7-benzyloxy-4-trifluoromethylcoumarin as the marker substrate with an IC50 value of 1.8 µM. [23] Another group obtained an IC50 value of 31 ± 8 µM for apigenin using 7-benzyloxymethyloxy-3-cyanocoumarin as the marker substrate of cytochrome P450 3A4. [24] Use of different substrates for determining cytochrome P450 3A4 enzyme activity can explain observed differences in IC50 values between studies.…”

Protection of Apigenin against Kainate-Induced Excitotoxicity by Anti-oxidative Effects

“…18) In addition, apigenin has demonstrated anticonvulsant effects in picrotoxin-induced rats. 20) Despite the widespread use of apigenin, 21) knowledge of its mechanism of action or protective effects on glutamate-mediated toxicity is limited. In this study, to elucidate these issues, we investigated the protective effects and possible mechanism of apigenin induced by excitotoxicity in hippocampal neurons.…”

Chemoprotective and chemosensitizing effects of apigenin on cancer therapy

“…To improve the efficiency of oral delivery of PTX, some investigations have been performed by the suppression of ABCB1 and metabolic enzymes. PTX is a substrate of ABCB1 and several studies have reported that its oral bioavailability was substantially increased by PTX coadministration with ABCB1 inhibitors [114]. As formerly mentioned, apigenin sensitized prostate [101], uterine [103], and breast [104] cancer cells to DOX by ABCB1 inhibition.…”

“…Apigenin also significantly increased the terminal half-life of PTX when it was used orally. Taken together, the improvement of oral bioavailability of PTX by apigenin might be due to enhanced intestinal absorption owing to ABCB1 inhibition by apigenin [114,115]. Xu et al showed that apigenin could sensitize different human cancer cells such as cervical epithelial carcinoma, lung epithelial carcinoma, and hepatocyte carcinoma cells to PTX through inducing apoptosis by suppressing SOD activity leading to accumulation of ROS and caspase-2 cleavage [116].…”