Research paper
Enhanced paclitaxel bioavailability after oral administration of paclitaxel or prodrug to rats pretreated with quercetin

https://doi.org/10.1016/j.ejpb.2003.11.002Get rights and content

Abstract

The aim of this study was to investigate the effect of quercetin on the bioavailability of paclitaxel after the oral administration of paclitaxel or a prodrug to rats pretreated with quercetin. Paclitaxel (40 mg/kg) and prodrug (280 mg/kg, 40 mg/kg as the paclitaxel) were administered orally to rats pretreated with quercetin (2, 10, 20 mg/kg). The plasma concentrations of paclitaxel pretreated with quercetin were increased significantly (P<0.01, for paclitaxel; P<0.05, for prodrug) compared to the control. The areas under the plasma concentration–time curve (AUC) and the peak concentrations (Cmax) of paclitaxel pretreated with quercetin were significantly higher (P<0.01) than the control. The half-life (t1/2) and mean residence times were significantly (P<0.05) longer compared to the control. The absolute bioavailability (AB%) of paclitaxel pretreated with quercetin was significantly higher (P<0.01) than the control. The AUC of paclitaxel after administration of the prodrug to rats pretreated with quercetin was significantly (P<0.05) higher than the prodrug control. The relative bioavailability of paclitaxel after administration of the prodrug to rats pretreated with quercetin was 1.25- to 2.02-fold higher than the prodrug control. The AB% of paclitaxel was increased significantly (P<0.05) by quercetin from 8.0 to 10.1 and 16.2%. The bioavailability of paclitaxel administered as a prodrug with or without pretreatment of quercetin was remarkably higher than the control. AUC, AB% and Cmax of paclitaxel after administration of the paclitaxel or prodrug pretreated with quercetin for 3 days were much higher than those administered after 20 min. It might have resulted from the physicochemical properties of the prodrug, which is a water-soluble compound and passes through the gastrointestinal mucosa more easily than paclitaxel without obstruction of P-gp and cytochrome P-450 in the gastrointestinal mucosa. It seems that the development of oral paclitaxel preparations as a prodrug or with quercetin is feasible, which is more convenient than the i.v. dosage forms.

Introduction

Paclitaxel (Taxol®) is an antineoplastic agent that is derived from the bark of the Pacific yew tree (Taxus brevifolia) [1]. In contrast to Vinca alkaloids, the anticancer action of taxol is that it inhibits cellular growth by promoting and stabilizing the microtubule assembly by a non-covalent interaction with tubulin, which blocks cell replication in the late G2 mitotic phase of the cell cycle [2], [3]. Because of its poor water solubility, paclitaxel is currently formulated as taxol and a mixture of polyoxyethyleneglycerol triricinoleate 35 (Cremophor EL) and dehydrated ethanol USP (1:1, v/v) for the i.v. dosage form. Cremephor EL itself is toxic and produces vasodilation, labored breathing, lethargy and hypotension when administered intravenously. One mediator of the hypersensitivity reactions is the endogenous histamine release, and prophylaxis to counteract the histaminergic mechanisms reduces the incidence of the hypersensitivity reactions [4]. Paclitaxel has been used to treat ovarian carcinoma, breast carcinoma, leukemia, melanoma, prostate carcinoma, etc., and has become particularly important in managing ovarian and breast carcinoma [5], [6], [7], [8]. The oral administration of the paclitaxel is problematic as it has poor absorption due to the poor solubility and efflux pump function of the drug for the multidrug transporter P-glycoprotein (P-gp), which is present abundantly in the gastrointestinal tract. Thus, this drug is mainly used for i.v. administration [9].

Paclitaxel has a very large volume of distribution in the body, and is highly bound by plasma protein, primarily albumin (95–98%) [10]. In particular, it is much higher in disposition of the liver and bile than in the other tissues [11]. Less than 6–10% of administered paclitaxel is recovered as the unchanged drug in the urine of treated patients [10], [12], [13]. Paclitaxel is mainly metabolized through the liver and undergoes biliary excretion [14], [15], [16], [17]. In humans, the total fecal excretion is approximately 70% of the paclitaxel dose, with 6α-hydroxypaclitaxel being the major metabolite [18].

In an attempt to develop safer formulations, many studies have been directed towards a new oral formulation. However, paclitaxel is very poorly absorbed when administered orally. Several studies have reported that the poor bioavailability of paclitaxel would result from the metabolism by enzymes or counter-transport processes by P-gp in the gut wall. It has been suggested that, in some cases the poor absorption of drugs after oral administration results from the activity of a multidrug transporter, a membrane-bound P-gp, which functions as an energy-dependent transporter or an efflux pump to decrease the intracellular accumulation of the drugs by extruding xenobiotics from the cell [9].

Flavonoids are regarded as a new class of chemosensitizers, which interact with both the cytosolic domains of P-gp and its ATP binding site [19]. It also has been reported to act as various CYP enzyme inhibitors or antioxidant agents [20].

Quercetin as a member of the flavonoids class, has been reported to possess the ability to inhibit the P-gp pump efflux [21]. It also has been reported that quercetin can inhibit CYP 3A, which is the main subfamily of the cytochrome P-450 that is responsible for metabolizing paclitaxel as 6α-hydroxytaxol [15]. In addition, it can competitively inhibit CYP 2A8, which induces the formation of 6α-hydroxytaxol [16].

This study introduces a water-soluble prodrug compound, 7-mPEG 5000-succinyloxymethyloxycarbonyl-paclitaxel, which combines a water-soluble polymer with paclitaxel [22]. It is rapidly hydrolyzed by an esterase to generate the physiologically active paclitaxel. The aim of this study was to investigate oral paclitaxel preparations, which will be more convenient than the i.v. dosage form, in an attempt to enhance the bioavailability of paclitaxel co-administered paclitaxel or a prodrug with quercetin orally in rats.

Section snippets

Materials

Paclitaxel was purchased from Brystol-Myers Squibb Co. (NY, USA). Saline (0.9% NaCl injectable solution) was obtained from Choongwae Co. (Seoul, Korea). Acetonitrile, methanol, tert-butylmethylether were acquired from Merck Co. (Darmstadt, Germany). Quercetin and n-butyl p-hydroxybenzoate (butylparaben) were purchased from the Sigma Chemical Co. (St Louis, MO). Phosphoric acid was obtained from the Junsei Co. (Tokyo, Japan). The other chemicals were of reagent grade and were used without

Results and discussion

The plasma profiles of paclitaxel after oral administration of the paclitaxel control (40 mg/kg) and the prodrug (280 mg, 40 mg as the paclitaxel) in animals pretreated with various doses of quercetin (2, 10, 20 mg/kg) are shown in Fig. 1, Fig. 2. The bioavailability and the pharmacokinetic parameters of paclitaxel after the administration of paclitaxel or prodrug pretreated with quercetin are shown in Table 1, Table 2. When paclitaxel (40 mg/kg) or prodrug (280 mg/kg) were administered with

Acknowledgements

This work was supported by Kolon Inc. (Seoul, Korea).

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