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Drug Metabolism and Disposition Fast Forward
First published on July 28, 2005; DOI: 10.1124/dmd.105.005892

0090-9556/05/3311-1580-1583$20.00
DMD 33:1580-1583, 2005

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SHORT COMMUNICATION

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

Johanna Weiss, Alexandra Sauer, Andreas Frank, and Matthias Unger

Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany (J.W., A.S.); and Institute of Pharmacy and Food Chemistry, Department of Pharmaceutical Chemistry, University of Würzburg, Würzburg, Germany (A.F., M.U.)

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 Due to reported cases of liver toxicity, kava-kava extracts were withdrawn from the market in several countries in 2002.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 P-gp-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 f2 (concentration needed to double baseline fluorescence) values of 170 µg/ml and 17 to 90 µM, respectively. The f2 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.

Address correspondence to: Dr. Johanna Weiss, Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany. E-mail: johanna_weiss{at}med.uni-heidelberg.de




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