Pharmacokinetic drug interactions between apigenin, rutin and paclitaxel mediated by P-glycoprotein in rats

Abstract

The aim of present study was to investigate the effects of apigenin and rutin on the pharmacokinetics of paclitaxel after oral administration of paclitaxel with apigenin and rutin to rats. Paclitaxel (40 mg/kg) was administered orally alone and in combination with apigenin and rutin (10, 20, and 40 mg/kg) for 15 consecutive days. In the single-dose pharmacokinetic study (SDS), blood samples were collected on 1st day whereas on 15th day in the multiple-dose pharmacokinetic study (MDS). The plasma concentrations of paclitaxel were increased dose-dependently in the combination of apigenin and rutin compared to that of paclitaxel control in SDS and MDS (p < 0.01). The areas under the plasma concentration-time curve (AUC) and the plasma peak concentrations (C max) of paclitaxel with apigenin and rutin were significantly higher (p < 0.01) than that of the control. The AUCs and C max of paclitaxel were increased with apigenin and rutin in the dose-dependent manner. The half-life (t 1/2) was significantly longer than that of the control. Non-everted sacs were filled with paclitaxel 100 μM in the presence and absence of verapamil (50 μM), apigenin, and rutin (50, 100 μM) and incubated at 37 ºC for 60 min. The absorption of paclitaxel was increased in the presence of apigenin, rutin, and verapamil, a typical P-glycoprotein and Cyp3A4 inhibitor. If these results are confirmed in humans in a clinical setting, the paclitaxel dose should be adjusted when it is given concomitantly with apigenin and rutin.

The therapeutic effects of apigenin and dexamethasone on 5‐fluorouracil‐induced oral mucositis – a pilot study using a Syrian hamster model

“…Apigenin [99% high‐performance liquid chromatography (HPLC)] (Sigma‐Aldrich, Madrid, Spain) was administered at a dose of 40 mg/Kg and a concentration of 8.8 mg/ml, following up on Kumar et al study . 5‐Fluorouracil ≥99% (HPLC) (Sigma‐Aldrich) was administered at a dose 60 mg/Kg at a concentration of 50 mg/ml.…”

Dietary polyphenols influence antimetabolite agents: methotrexate, 6-mercaptopurine and 5-fluorouracil in leukemia cell lines

“…This is equivalent to a 7.6 μM plasma concentration, which is comparable to the levels used in this study. Likewise, oral administration of apigenin has also been shown to alter the bioavailability of paclitaxel in rats, which demonstrates apigenin can alter systemic effects of chemotherapeutics [ 46 ]. Finally, plasma-levels of quercetin, derived from dietary sources, have also been shown to inhibit the efficacy of the proteasome inhibitor, bortezomib in chronic lymphocytic leukaemia cells [ 47 ].…”

Effects of Jia‐Wei‐Xiao‐Yao‐San on the Peripheral and Lymphatic Pharmacokinetics of Paclitaxel in Rats

“…Chinese herbal medicines, including Astragalus, Turmeric, Ginseng, TJ-41, PHY-906, Huachansu infection, and Kanglaite injection, are commonly used by patients for cancer treatment and/or for the reduction of toxicity associated with chemotherapy and radiotherapy [ 29 ]. Studies on pharmacokinetic interactions between Chinese herbal medicines and Western medicines [ 5 , 11 , 13 , 30 ] have been conducted, and the results suggest that oral administration of some phenolic substances might increase paclitaxel blood concentrations during chemotherapy. Because paclitaxel is a P-gp substrate, investigation on P-gp inhibition on the mesenteric lymphatic transport of paclitaxel has been reported [ 31 ].…”