Pharmacokinetics and Disposition of the Kavalactone Kawain: Interaction With Kava Extract and Kavalactones in Vivo and in Vitro

Mathews, James; Etheridge, Amy S.; Valentine, J L; Black, Sherry R; Coleman, Donna P.; Patel, Purvi R.; So, J; Burka, Leo T.

doi:10.1124/dmd.105.004317

Cited by 75 publications

(81 citation statements)

References 15 publications

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“…These results suggest that the kavalactone components, rather than other components of the extract, are responsible for the inhibition of CYP450 isozymes. Inhibition of CYP450 isozymes is believed to be the most likely factor in causing kava-mediated adverse drug reactions via inhibition of drug metabolism (77,78).…”

Section: Alteration Of Cytochrome P450 Metabolizing Isozymes-it Has Bmentioning

confidence: 99%

Toxicity of Kava Kava

Xia

Guo

et al. 2008

Journal of Environmental Science and Health, Part C

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Kava is a traditional beverage of various Pacific Basin countries. Kava has been introduced into the mainstream U.S. market principally as an anti-anxiety preparation. The effects of the long-term consumption of kava have not been documented adequately. Preliminary studies suggest possible serious organ system effects. The potential carcinogenicity of kava and its principal constituents are unknown. As such, kava extract was nominated for the chronic tumorigenicity bioassay conducted by the National Toxicology Program (NTP). At present toxicological evaluation of kava extract is being conducted by the NTP. The present review focuses on the recent findings on kava toxicity and the mechanisms by which kava induces hepatotoxicity. KeywordsKava; anti-anxiety herbal beverage; top-selling botanical; hepatotoxicity; metabolism; mechanism Kava, prepared from the rhizome of the kava tropical shrub plant, Piper methysticum Forst F., is a traditional beverage used for many centuries, especially at ceremonial activities in the South Pacific (1-6). During recent years, kava has been used in Europe for treatment of anxiety and nervous disorders such as stress and restlessness, and in the United States as a natural alternative to anti-anxiety drugs and sleeping pills (6). Kava sales totaled more than $ 100 million in 1998, being the fifth leading seller of the North American botanicals (7).The association between the use of kava products and hepatotoxicity has prompted many countries, including Germany, Switzerland, France, Canada, and the United Kingdom, to take regulatory actions, ranging from warning consumers to removing kava-containing products from the marketplace. On March 25, 2002, the Center for Food Safety and Applied Nutrition (CFSAN), U.S. Food and Drug Administration (FDA) issued a Consumer Advisory entitled "Kava-containing dietary supplements may be associated with severe liver injury" to the public (8, 9). Kava-containing products remain popular in the United States and continue to be sold in health food stores and ethnic markets regardless of the fact that it Address correspondence to Peter P. Fu, National Center for Toxicological Research, Jefferson, AR 72079. peter.fu@fda.hhs.gov; chanp@niehs.nih.gov. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript was banned in Germany, France, Switzerland, Australia, and Canada (10). In this review, human exposure and metabolism of kava are briefly addressed, recent findings on the toxicity of kava are reported, and possible mechanisms by which kava induces toxicity are described. CHEMICAL COMPOSITIONThe kava plant, belonging to the Piperacae family, is widely cultivated in the South Pacific.Kava is cultivated for its rootstock. Depending upon the amount of kavalactones contained in the resin, the rootstock shows different color, varying from white to dark yellow (2,5,6). Fresh kava rootstock contains about 80% water. Dried rootstock consists of about 43% starch, 20% fibers, 12% water, 3-4% proteins, 3% sugars, 3% minerals, ...

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Section: Alteration Of Cytochrome P450 Metabolizing Isozymes-it Has Bmentioning

confidence: 99%

Toxicity of Kava Kava

Xia

Guo

et al. 2008

Journal of Environmental Science and Health, Part C

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“…Since the 1990s, commercial kava extracts formulated as tablets and/or capsules have been marketed as dietary supplements for the alleviation of stress, anxiety, or insomnia (Côté et al, 2004;Ulbricht et al, 2005). The kavalactones (kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin), a collection of phytochemicals unique to kava, have also been shown to modulate P-gp activity in vitro (Mathews et al, 2005;Weiss et al, 2005).…”

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confidence: 99%

Effect of Goldenseal (Hydrastis canadensis) and Kava Kava (Piper methysticum) Supplementation on Digoxin Pharmacokinetics in Humans

et al. 2006

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ABSTRACT:Phytochemical-mediated modulation of P-glycoprotein (P-gp) and other drug transporters may give rise to many herb-drug interactions. Serial plasma concentration-time profiles of the P-gp substrate, digoxin, were used to determine whether supplementation with goldenseal or kava kava modified P-gp activity in vivo. Twenty healthy volunteers were randomly assigned to receive a standardized goldenseal (3210 mg daily) or kava kava (1227 mg daily) supplement for 14 days, followed by a 30-day washout period. Subjects were also randomized to receive rifampin (600 mg daily, 7 days) and clarithromycin (1000 mg daily, 7 days) as positive controls for P-gp induction and inhibition, respectively. Digoxin (Lanoxin, 0.5 mg) was administered p.o. before and at the end of each supplementation and control period. Serial digoxin plasma concentrations were obtained over 24 h and analyzed by chemiluminescent immunoassay. Comparisons of area under the curve (AUC) (0-3) , AUC (0-24) , C max, CL/F, and elimination half-life were used to assess the effects of goldenseal, kava kava, rifampin, and clarithromycin on digoxin pharmacokinetics. Rifampin produced significant reductions (p < 0.01) in AUC (0-3) , AUC (0-24) , CL/F, t 1/2 , and C max , whereas clarithromycin increased these parameters significantly (p < 0.01). With the exception of goldenseal's effect on C max (14% increase), no statistically significant effects on digoxin pharmacokinetics were observed following supplementation with either goldenseal or kava kava. When compared with rifampin and clarithromycin, supplementation with these specific formulations of goldenseal or kava kava did not appear to affect digoxin pharmacokinetics, suggesting that these supplements are not potent modulators of P-gp in vivo.

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“…These findings suggest inhibition of the metabolism of NFP mainly in the liver on the co-administration of EK-114. Some constituents, but not glycyrrhizin, included in the extract of Glycyrrhiza in the pharmacokinetics of kawain itself, a constituent of the extract (Mathews et al, 2005). Different effects of a single and repeated administration were demonstrated for other natural products.…”

Section: Discussionmentioning

confidence: 99%

Effects of Sairei‐to on the pharmacokinetics of nifedipine in rats

Ikehata

Ohnishi

Matsumoto

et al. 2007

Phytotherapy Research

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Sairei-to is a traditional herbal medicine used to complement, and as an alternative to, Western drugs. The aim of this study was to evaluate the pharmacokinetic interactions between Sairei-to and nifedipine (NFP), a substrate for CYP3A, in rats. NFP-oxidizing activity and the pharmacokinetics of NFP were examined after a single or 1-week of administration of Sairei-to (EK-114). NFP-oxidizing activity was enhanced transiently around 24 h after a single administration of EK-114 (1400 mg/kg). In vivo, the first-pass metabolism of NFP increased in the small intestine at 24 h after the administration of EK-114, and this effect disappeared at 72 h. Co-administration of EK-114 tended to inhibit the metabolism of NFP. On the other hand, when EK-114 was given at a high dose (1400 mg/kg) for 1 week, the oxidation of NFP in the small intestine was inhibited, and C max and AUC after the oral administration of NFP increased. In addition, a clinical dose of EK-114 (140 mg/ kg) did not alter the pharmacokinetics of NFP, regardless of the administration schedule. EK-114 was suggested to affect the metabolism of NFP. However, the CYP3A-mediated pharmacokinetic interaction on the concomitant use of EK-114 may not be clinically significant.

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Pharmacokinetics and Disposition of the Kavalactone Kawain: Interaction With Kava Extract and Kavalactones in Vivo and in Vitro

Cited by 75 publications

References 15 publications

Toxicity of Kava Kava

Toxicity of Kava Kava

Effect of Goldenseal (Hydrastis canadensis) and Kava Kava (Piper methysticum) Supplementation on Digoxin Pharmacokinetics in Humans

Effects of Sairei‐to on the pharmacokinetics of nifedipine in rats

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