Pharmacokinetics and disposition of the kavalactone kawain: interaction with kava extract and kavalactones in vivo and in vitro.
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 microM. Kava extract and kavalactones (< or =9 microM) modestly stimulated P-glycoprotein ATPase activities. Taken together, the data indicate that kava can cause adverse drug reactions via inhibition of drug metabolism.
Mathews
James M
JM
RTI International, P.O. Box 12194, 3040 Cornwallis Road, RTP, NC 27709, USA. mathews@rti.org
Etheridge
Amy S
AS
Valentine
John L
JL
Black
Sherry R
SR
Coleman
Donna P
DP
Patel
Purvi
P
So
James
J
Burka
Leo T
LT
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D014151:Anti-Anxiety Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D001682:Biological Availability; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D007275:Injections, Intravenous; D020901:Kava / Q000737:chemistry*; D007783:Lactones / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D010936:Plant Extracts / Q000493:pharmacokinetics / Q000494:pharmacology*; D011753:Pyrones / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D011916:Rats, Inbred F344
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014151:Anti-Anxiety Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D007783:Lactones; D010936:Plant Extracts; D011753:Pyrones; D003577:Cytochrome P-450 Enzyme System; D000251:Adenosine Triphosphatases; C011889:kavain