Traditional aqueous kava extracts inhibit cytochrome P450 1A2 in humans: Protective effect against environmental carcinogens?

Russmann, Stefan; Lauterburg, Bernhard H.; Barguil, Yann; Choblet, E.; Cabalion, Pierre; Rentsch, Katharina; Wenk, Markus R.

doi:10.1016/j.clpt.2005.01.021

Cited by 28 publications

(22 citation statements)

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“…Daily doses of kava commonly used in clinical trials for the treatment of anxiety (210 mg of kavalactones) (Jellin et al, 2002) are equivalent to about 3 mg/kg/day, but consumption of 1 to 4 g of kavalactones per day (ca. 60 mg/kg) has been reported for regular consumers of kava (Russmann et al, 2005). Accordingly, allowing for a reasonable allometric scaling factor between rat and human, a dose of 100 mg/kg was selected for the present studies in rat.…”

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confidence: 99%

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

Mathews¹,

Etheridge²,

Valentine³

et al. 2005

Drug Metab Dispos

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ABSTRACT:Reported adverse drug interactions with the popular herb kava have spurred investigation of the mechanisms by which kava could mediate these effects. In vivo and in vitro experiments were conducted to examine the effects of kava extract and individual kavalactones on cytochrome P450 (P450) and P-glycoprotein activity. The oral pharmacokinetics of the kavalactone, kawain (100 mg/kg), were determined in rats with and without coadministration of kava extract (256 mg/kg) to study the effect of the extract on drug disposition. Kawain was well absorbed, with >90% of the dose eliminated within 72 h, chiefly in urine. Compared with kawain alone, coadministration with kava extract caused a tripling of kawain AUC 0-8 h and a doubling of C max . However, a 7-day pretreatment with kava extract (256 mg /kg/day) had no effect on the pharmacokinetics of kawain administered on day 8. The 7-day pretreatment with kava extract only modestly induced hepatic P450 activities. The human hepatic microsomal P450s most strongly inhibited by kava extract (CYP2C9, CYP2C19, CYP2D6, CYP3A4) were inhibited to the same degree by a "composite" kava formulation composed of the six major kavalactones contained in the extract. K i values for the inhibition of CYP2C9 and CYP2C19 activities by methysticin, dihydromethysticin, and desmethoxyyangonin ranged from 5 to 10 M. Kava extract and kavalactones (<9 M) modestly stimulated P-glycoprotein ATPase activities. Taken together, the data indicate that kava can cause adverse drug reactions via inhibition of drug metabolism.

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confidence: 99%

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

Mathews¹,

Etheridge²,

Valentine³

et al. 2005

Drug Metab Dispos

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“…For kava-kava there are several reports of liver toxicity (Teschke et al, 2003;Anke and Ramzan, 2004a,b;Clouatre, 2004), which might be due to interactions with simultaneously applied drugs. Several studies have demonstrated the inhibition of P450s by kava-kava and its components in vitro (Unger et al, 2002;Côté et al, 2004;Unger and Frank, 2004;Zou et al, 2004) and in vivo (Gurley et al, 2005;Russmann et al, 2005) but, hitherto, no data were available on the interaction of kava-kava with P-gp.…”

Section: Discussionmentioning

confidence: 99%

“…The reason for the observed liver toxicity is unknown. It has been suggested that the extraction process of the crude root powder results in chemical changes that may be related to hepatotoxicity in some preparations (Whitton et al, 2003), but interactions with other drugs or herbal supplements might also be the underlying cause.Several human cytochrome P450 isoenzymes (P450s) are inhibited by kava-kava extracts and kavalactones in vitro (Unger et al, 2002;Côté et al, 2004;Unger and Frank, 2004;Zou et al, 2004) and in vivo (Gurley et al, 2005;Russmann et al, 2005). Hence, interactions at the level of P450s are conceivable.…”

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confidence: 99%

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EXTRACTS AND KAVALACTONES OF PIPER METHYSTICUM G. FORST (KAVA-KAVA) INHIBIT P-GLYCOPROTEIN IN VITRO

Weiß¹,

Sauer²,

Frank³

et al. 2005

Drug Metab Dispos

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ABSTRACT:Root extracts from kava-kava (Piper methysticum G. Forst) are clinically used for the treatment of anxiety and restlessness. Due to reported cases of liver toxicity, kava-kava extracts were withdrawn from the market in several countries in 2002. Because the efflux transporter P-glycoprotein (P-gp) is involved in the absorption, distribution, and excretion of many drugs and often participates in drug-drug interactions, we studied the effect of a crude kava extract and the main kavalactones kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin on the P-gp-mediated efflux of calcein-acetoxymethylester in the Pgp-overexpressing cell line P388/dx and the corresponding cell line P388. The crude extract and the kavalactones showed a moderate to potent inhibitory activity with f 2 (concentration needed to double baseline fluorescence) values of 170 g/ml and 17 to 90 M, respectively. The f 2 value of yangonin could not be determined due to its higher lipophilicity. In conclusion, our results for the first time demonstrate P-gp-inhibitory activity of kava-kava and its components in vitro.Extracts made from the root-stock of kava-kava (Piper methysticum G. Forst), a perennial shrub native to the South Pacific Islands, are traditionally used for their calming and relaxing effects. For over a decade, commercial kava-kava extracts have been marketed as dietary supplements for the treatment of stress, insomnia, and anxiety (Côté et al., 2004). The kavalactones (kavapyrones) kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin are the main ingredients and were found to be the major pharmacologically active principle (Singh and Singh, 2002). Therefore, extracts are standardized to a certain amount of kavalactones. In 2002, kavakava extracts were withdrawn from the market in Germany, United Kingdom, France, Switzerland, Australia, and Canada due to reported cases of liver toxicity (Teschke et al., 2003; Anke and Ramzan, 2004a,b;Clouatre, 2004). The reason for the observed liver toxicity is unknown. It has been suggested that the extraction process of the crude root powder results in chemical changes that may be related to hepatotoxicity in some preparations (Whitton et al., 2003), but interactions with other drugs or herbal supplements might also be the underlying cause.Several human cytochrome P450 isoenzymes (P450s) are inhibited by kava-kava extracts and kavalactones in vitro (Unger et al., 2002;Côté et al., 2004;Unger and Frank, 2004;Zou et al., 2004) and in vivo (Gurley et al., 2005;Russmann et al., 2005). Hence, interactions at the level of P450s are conceivable. ABC-transporters, especially P-glycoprotein (P-gp), are another possible site of interaction. P-gp, the product of the MDR1/ABCB1 gene, is involved in the absorption, distribution, and excretion of many drugs (Schinkel and Jonker, 2003). Clinically relevant drug interactions are possible if the plasma or tissue concentrations of drugs with a narrow therapeutic range are increased or de...

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“…Kava may also inhibit CYP1A2 activity, based on a study conducted in 6 regular consumers of traditional aqueous kava extract; the other isozymes CYP2C19, -3A4, -2D6, and -2E1 were not altered in these consumers. 163 Kava may also modify Pgp transport. 164 Twenty healthy volunteers were given 75-mg capsules of kavalactones 3 times a day (1227 mg/d) for 14 days.…”

Section: Human and Clinical Studiesmentioning

confidence: 99%

Drug—Botanical Interactions: A Review of the Laboratory, Animal, and Human Data for 8 Common Botanicals

2009

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Many Americans use complementary and alternative medicine (CAM) to prevent or alleviate common illnesses, and these medicines are commonly used by individuals with cancer. These medicines or botanicals share the same metabolic and transport proteins, including cytochrome P450 enzymes (CYP), glucuronosyltransferases (UGTs), and P-glycoprotein (Pgp), with over-thecounter and prescription medicines increasing the likelihood of drug-botanical interactions. This review provides a brief description of the different proteins, such as CYPs, UGTs, and Pgp. The potential effects of drug-botanical interactions on the pharmacokinetics and pharmacodynamics of the drug or botanical and a summary of the more common models used to study drug metabolism are described. The remaining portion of this review summarizes the data extracted from several laboratory, animal, and clinical studies that describe the metabolism, transport, and potential interactions of 8 selected botanicals. The 8 botanicals include black cohosh, Echinacea, garlic, Gingko biloba, green tea, kava, milk thistle, and St John's wort; these botanicals are among some of the more common botanicals taken by individuals with cancer. These examples are included to demonstrate how to interpret the different studies and how to use these data to predict the likelihood of a clinically significant drug-botanical interaction.

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Traditional aqueous kava extracts inhibit cytochrome P450 1A2 in humans: Protective effect against environmental carcinogens?

Cited by 28 publications

References 4 publications

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

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

EXTRACTS AND KAVALACTONES OF PIPER METHYSTICUM G. FORST (KAVA-KAVA) INHIBIT P-GLYCOPROTEIN IN VITRO

Drug—Botanical Interactions: A Review of the Laboratory, Animal, and Human Data for 8 Common Botanicals

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