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First published on July 20, 2005; DOI: 10.1124/dmd.105.004317

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James M Mathews
Amy S Etheridge
John L Valentine
Sherry R Black
Donna P Coleman
Purvi R Patel
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Received for publication March 2, 2005.
Revised June 17, 2005.
Accepted for publication July 20, 2005.

PHARMACOKINETICS AND DISPOSITION OF THE KAVALACTONE KAWAIN: INTERACTION WITH KAVA EXTRACT AND KAVALACTONES IN VIVO AND IN VITRO

James M Mathews 1*, Amy S Etheridge 1, John L Valentine 1, Sherry R Black 1, Donna P Coleman 1, Purvi R Patel 1, James So 1, Leo T Burka 2

1 Research Triangle Institute 2 National Institute of Environmental Health Sciences

* Address correspondence to: E-mail: mathews{at}rti.org

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 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 to kawain alone, coadministration with kava extract caused a tripling of kawain AUC0-8 h and a doubling of Cmax. 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. Ki values for the inhibition of CYP2C9 and CYP2C19 activities by methysticin, dihydromethysticin, and desmethoxyyangonin ranged from 5-10 µM. Kava extract and kavalactones (≤9 µM.) modestly stimulated P-glycoprotein ATPase activities. Taken together, the data indicate that kava can cause adverse drug reactions via inhibition of drug metabolism.


Key words: bioavailability, CYP induction, CYP inhibition, drug absorption, drug disposition, human CYP enzymes, liver microsomes


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