Lethal quercetin-digoxin interaction in pigs
Introduction
Digoxin is one of cardiac glycosides with very narrow therapeutic range (0.8–2.0 ng/ml) and the intensifying myriad of interactions. P-gp (P-glycoprotein) mediated digoxin transport was demonstrated in rats (Su and Huang, 1996). It was established that the absorption of digoxin as well as the direct intestinal secretion of digoxin was dependent on intestinal P-gp. Digoxin is extensively metabolized in rats and it is recently shown that cytochrome P450 3A (CYP 3A) is the primary enzyme family involved (Salphati and Benet, 1999). In contrast to rats, digoxin is a substrate for P-gp but not for CYP 3A enzyme in humans, therefore, digoxin exhibited remarkably different pharmacokinetics between rats and humans (Harrison and Gibaldi, 1976). Our preliminary study indicated that the pharmacokinetic behavior of digoxin in pigs had greater resemblance with that in humans and very different from that in rats.
In recent decades, flavonoids exhibited a wide range of beneficial biological activities including antioxidative, radical scavenging, anti-inflammatory, antiatherosclerotic, antitumor and antiviral effects (Nijveldt et al., 2001). Quercetin is an ubiquitous flavonoid distributed in plant foods, beverage, herbs and dietary supplements, e.g. onions, grapes, berries, apples, red wine, tea, St. John's wort and ginkgo. In addition to its various activities, quercetin has attracted increasing interest because of its abilities to modulate CYP 3A4 and P-gp. The significant role of CYP 3A4 for drug–drug interactions was well recognized, whereas the role of P-gp for chemoprevention of organisms and drug–drug interaction had been proposed Bosch and Croop, 1996, Ducharme et al., 1993, Ducharme et al., 1995. Regarding to the modulation of quercetin on P-gp, it has been initially identified as an inducer in multidrug-resistant breast cancer cells and HCT-15 colon cells Phang et al., 1993, Critchfiels et al., 1994, but later it was reported to be an inhibitor of Hoechst 33342 transport by P-gp (Shapiro and Ling, 1997). We recently found that quercetin significantly inhibited the activity of intestinal P-gp in an everted rat gut sac (Hsiu et al., 2002).
Quercetin is the most predominant flavonoid in the human diet. The daily dietary intake of quercetin is estimated to be in the range of 4 to 68 mg based on epidemiological studies in the U.S., Europe, and Asia Knekt et al., 1997, Hertog et al., 1995, Hertog et al., 1993, Rimm et al., 1996 but can be as high as several hundred mg in dietary supplement and several grams in anticancer therapy (Lamson and Brignall, 2000). Therefore, this study attempted to use pig as model to investigate the effect of coadministration of quercetin (50 mg/kg and 40 mg/kg) on the absorption and disposition of digoxin.
Section snippets
Reagents
Digoxin was kindly offered by Yung-Shin Co. (Taichung county, Taiwan, R.O.C.). Quercetin (95% purity) and glycofurol were obtained from Sigma Chemical Co. (St. Louis, MO., U.S.A.). TDx kit for digoxin was purchased from Abbott Laboratories (Abbott Park, Ill., U.S.A).
Animals and drug administration
Six male Yorkshire pigs (30–50 kg) obtained from the Animal Technology Institute, Taiwan (Miaoli, Taiwan, R.O.C.) were fasted for 12 h before drug administration and food was withheld for another 8 h. Digoxin was dissolved in water
Results
Initially a total of six pigs were used for investigating the effect of coadministration of 50 mg/kg quercetin on the biological fate of digoxin in a crossover design. Three pigs received digoxin with quercetin, and the other three received digoxin alone in the first treatment according to the protocol. Unexpectedly, within 30 min after drug administration, two of the three pigs receiving combined therapy died suddenly, and the third pig suffered from typical mild symptoms of acute digoxin
Discussion
The results revealed a clear indication that quercetin significantly enhanced the absorption of digoxin in pigs. In contrast to the influence of quercetin on cyclosporin pharmacokinetics reported recently, the biological fate of cyclosporin was affected differently by quercetin (Hsiu et al., 2002). Cyclosporin is a substrate for both CYP 3A4 and P-gp, whereas digoxin in pigs might be a substrate for P-gp but not for CYP 3A4 as in humans, presumed from the similar elimination half-life of
Acknowledgements
This work was supported by National Science Council, R.O.C. (NSC 91-2320-B-039-024), Committee on Chinese Medicine and Pharmacy, Department of Health, R.O.C. (CCMP92-RD-003), and China Medical University, R.O.C. (CMC91-CM-07).
References (25)
- et al.
P-glycoprotein, multidrug resistance and cancer
Biochimica et Biophysica Acta
(1996) - et al.
Inhibition of drug transport by genistein in multidrug-resistant cells expressing P-glycoprotein
Biochemical Pharmacology
(1997) - et al.
Effects of flavonols on P-glycoprotein activity in cultured rat hepatocytes
Life Science
(1995) - et al.
Considerations in the design and development of transport inhibitors as adjuncts to drug therapy
Advanced Drug Delivery Reviews
(2003) - et al.
Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly study
Lancet
(1993) - et al.
Quercetin significantly decreased cyclosporin oral bioavailability in pigs and rats
Life Science
(2002) Drug-drug interaction mediated by inhibition and induction of P-glycoprotein
Advanced Drug Delivery Reviews
(2003)- et al.
Effect of bioflavonoids on vincristine transport across blood-brain barrier
European Journal of Pharmacology
(2000) - et al.
Flavonoids: a review of probable mechanisms of action and potential applications
American Journal of Clinical Nutrition
(2001) - et al.
Effect of quercetin on Hoechst 33342 transport by purified and reconstituted p-glycoprotein
Biochemical Pharmacology
(1997)
Flavonoids in herbs: biological fates and potential interactions with xenobiotics
Journal of Food and Drug Analysis
Modulation of adriamycin accumulation and efflux by flavonoids in HCT-15 colon cells
Biochemical Pharmacology
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