Elsevier

Food and Chemical Toxicology

Volume 44, Issue 9, September 2006, Pages 1572-1578
Food and Chemical Toxicology

Marked decrease of cyclosporin bioavailability caused by coadministration of ginkgo and onion in rats

https://doi.org/10.1016/j.fct.2006.04.008Get rights and content

Abstract

Quercetin was reported to modulate CYP isoenzymes and P-glycoprotein (Pgp), a drug efflux transporter. Our previous study reported that quercetin significantly decreased the bioavailability of cyclosporin, a substrate for CYP3A4 and Pgp, in rats and pigs. Ginkgo and onion contain quercetin and its glycosides as St. John’s Wort. The coadministration of cyclosporin with ginkgo or onion may be subject to clinically relevant interactions as St. John’s Wort. Therefore, this study aimed to investigate the influences of ginkgo and onion on the absorption and disposition of cyclosporin in rats.

Cyclosporin was administered orally and intravenously to rats with and without an oral dose of ginkgo or onion in crossover designs. Blood samples were collected via cardiopuncture and blood cyclosporin concentration was assayed by a specific monoclonal fluorescence polarization immunoassay. Everted gut sac was used to investigate the effects of ginkgo and onion on the function of intestinal Pgp.

Oral coadministration of ginkgo and onion significantly decreased the Cmax of cyclosporin by 62% and 60%, and reduced the AUC0–t by 51% and 68%, respectively, whereas no influence was observed when cyclosporin was given intravenously. This indicates that the interactions between cyclosporin and ginkgo or onion occurred mainly at the absorption site.

In conclusion, ginkgo and onion markedly decreased the oral bioavailability of cyclosporin. We suggest that concurrent intake of quercetin-rich herbs or foods with cyclosporin are better avoided in order to ensure the efficacy of cyclosporin.

Introduction

In recent years, quercetin attracted great interest because of its various beneficial biological activities (Takahama, 1985, Ohnishi and Bannai, 1993, Murray, 1998, Alarcon-de-la-Lastra et al., 1994, Davis et al., 2000). Quercetin is widely distributed and predominantly present as glycosides in plant food, beverage and herbs (Liu and Sheu, 1989, Hertog et al., 1992, Hertog et al., 1995, Griffiths et al., 2002). Quercetin glycosides were known to be absorbed as quercetin through hydrolysis by lactase phloridizin hydrolase secreted by the small intestine (Daya et al., 2003) or β-glucosidase secreted by enterobacteria (Ioku et al., 1998). Quercetin was reported to modulate CYP 3A4 and Pgp, a drug efflux transporter, therefore, it might affect the bioavailability of drugs that are metabolized by CYP 3A4 or effluxed by Pgp (Miniscalco et al., 1992, Shapiro and Ling, 1997). Our previous study reported that quercetin significantly decreased the bioavailability of cyclosporin (Sandimmun®), a substrate of CYP 3A4 and Pgp (Kronbach et al., 1988, Lown et al., 1997, Edward et al., 1999) in pigs and rats (Hsiu et al., 2002). Furthermore, our rat model has demonstrated a similar interaction between St. John’s Wort (SJW) and cyclosporin (Yang et al., 2003) as clinical findings in humans (Ruschitzka et al., 2000, Barone et al., 2000).

Ginkgo is an herbal medicine, it becomes well-known worldwide for its possible benefits include support for memory loss, early Alzheimer’s disease (Perneczky and Kurz, 2004), therapy in tinnitus (Meyer, 1986) and depression (Fugh-Berman and Cott, 1999). EGb 761 is an extract from the leaves of Ginkgo biloba and is used widely for treating cerebral insufficiency in clinical therapy (Maurer et al., 1997, Oken et al., 1998). Many researches have reported that EGb 761 possesses beneficial activities including free radical scavenging, antagonist of platelet-activating factor, inhibition of monoamine oxidase and modulation on immune function (Ellnain-Wojtaszek et al., 2003, Porsolt et al., 2000, Puebla-Pérez et al., 2003). Ginkgo leaves contain glycosides of quercetin (including quercetin diglucoside, quercitrin, rutin), kaempferol, isorhamnetin, terpene trilactones, ascorbic acid, and d-glucaric acid. (Teris, 2002).

Onion is a daily diet. Nowadays, onion extract is sold as a dietary supplement and even available online for treatment of hypertension and hyperlipidemia. Onion has been reported to possess beneficial bioactivities including reduction of serum cholesterol, decrease of osteoporosis incidence, antithrombotic and anticancer effects (Campos et al., 2003, Jung et al., 2002, Muhlbauer and Li, 1999). Onion contains quercetin glycosides including quercetin 4′-glucoside, quercetin 7,4′-glucoside, quercetin 3,4′-glucoside, quercetin 3-glucoside, quercetin 7-glucoside, quercetin 3,7-glucoside, quercitrin, and rutin (Gee et al., 1998).

Cyclosporin is an important immunosuppressant with narrow therapeutic window. Maintenance of therapeutic cyclosporin concentrations following transplantation is critical to ensure adequate immunosuppression. Subtherapeutic cyclosporin concentrations can be associated with an increased risk of acute cellular rejection, while supratherapeutic concentrations can result in hepatotoxicity, nephrotoxicity and neurotoxicity (Edwards et al., 1995, Sijpkens et al., 2001, Voiculescu et al., 2003). Neoral® is the first microemulsion product which has improved immunosuppressive efficacy due to a better oral bioavailability, lower pharmacokinetic variability, and better dose-linearity in cyclosporin exposure compared with the former dosage form Sandimmun® (Dunn et al., 2001). Based on the common constituents, quercetin and its glycosides, contained in ginkgo and onion as well as in St. John’s Wort, the coadministration of cyclosporin with ginkgo or onion may be subject to clinically relevant interactions as with St. John’s Wort (Barone et al., 2000, Ruschitzka et al., 2000, Yang et al., 2003). This study attempted to investigate the influences of ginkgo and onion on the absorption and disposition of cyclosporin (Neoral®) in rats.

Section snippets

Materials

Cyclosporin (Neoral®, 100 mg/mL) was a gift from Novartis (Taiwan) Co. Ltd. and properly diluted with water before use. Ginkgo leaves were collected at Taichung County, Taiwan, in September 2001. Onion was purchased from a traditional market in Taichung City, Taiwan. Quercetin dihydrate was purchased from Sigma Chemical Co. (St. Louis, MO, USA). Rhodamine 123 was purchased from Aldrich Chemical Company (Milwakee, WI, USA). Milli-Q plus water (Millipore, Bedford, MA, USA) was used for all

Results

In order to measure the total quercetin, GD and OJ were hydrolyzed with acid. HPLC/UV method was developed for the determination of quercetin in the hydrolysates of GD and OJ. The present method showed satisfactory precision and accuracy, the recoveries of quercetin from GD and OJ were 92.4–109.0% and 100.8–109.7%, respectively. A significant increase of quercetin upon hydrolysis demonstrated the presence of quercetin glycosides. Table 1 lists the quercetin contents in the acid hydrolysates of

Discussion

Quercetin is present in onion and ginkgo mainly as glycosides, which is indispensable to be hydrolyzed by intestinal enzymes or enterobacteria before absorption by the small intestine (Victor and Winter, 1987). Because the authentic standards of quercetin glycosides are often not commercially available, therefore, acid hydrolysis was conducted in order to measure the total contents of quercetin (including quercetin and its glycosides) in GD and OJ. The strategy for protecting released quercetin

Acknowledgements

This work was supported by the National Science Council, ROC (NSC 92-2751-B-039-004-Y) and the China Medical University, Taichung, Taiwan, ROC (CMC91-P-05).

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