Abstract
Inhibitors of cytochrome P450 3A4 (CYP3A4) were identified in crude extracts from the rhizomes of Piper methysticum G. Forst. (Kava-Kava) using bioassay-guided fractionation. After preliminary purification of an ethyl acetate extract with solid phase extraction, the eluate was further fractionated by means of HPLC and fractions were tested for inhibitory potency using cDNA expressed CYP3A4. Positive fractions were analysed with LC/MS using electrospray ionisation and kavapyrones could be identified as the main CYP3A4 inhibitory components of Piper methysticum.
References
-
1 Blumenthal M. The complete German Commission E monographs. Integrative medicine communications. Boston, Massachusetts;
-
2
Escher M, Desmeules J, Giostra E, Mentha G.
Hepatitis associated with Kava, a herbal remedy for anxiety.
BMJ.
2001;
322
139
-
3
Kraft M. et al .
Fulminant liver failure after administration of the herbal antidepressant Kava-Kava.
Dtsch Med Wochenschr.
2001;
126
970-2
-
4
Russmann S, Lauterburg B H, Helbling A.
Kava hepatoxicity.
Ann Intern Med.
2001;
135
68-9
-
5
Stevinson C, Huntley A, Ernst E.
A systematic review of the safety of kava extract in the treatment of anxiety.
Drug Saf.
2002;
25
251-61
-
6
Schmidt M, Nahrstedt A.
Ist Kava lebertoxisch?.
Dtsch Apoth Ztg.
2002;
9
1006-11
-
7
Ernst E.
Safety concerns about kava.
Lancet.
2002;
359
1865
-
8
Benet L Z, Izumi T, Zhang Y, Silverman J A, Wacher V J.
Intestinal MDR transport proteins and P-450 enzymes as barriers to oral drug delivery.
J Control Release.
1999;
62
25-31
-
9
Gorski J C, Hall S D, Jones D R, VandenBranden M, Wrighton S A.
Regioselective biotransformation of midazolam by members of the human cytochrome P450 3A (CYP3A) subfamily.
Biochem Pharmacol.
1994;
47
1643-53
-
10
Wang R W, Newton D J, Scheri T D, Lu A Y.
Human cytochrome P450 3A4-catalyzed testosterone 6 beta-hydroxylation and erythromycin N-demethylation. Competition during catalysis.
Drug Metab Dispos.
1997;
25
502-7
-
11
Yun C H, Okerholm R A, Guengerich F P.
Oxidations of the antihistaminic drug terfenadine in human liver microsomes. Role of cytochrome P-450 3A(4) in N-dealkylation and C-hydroxylation.
Drug Metab Dispos.
1993;
21
403-9
-
12
Obach R S.
Inhibition of human cytochrome P450 enzymes by constituents of St. John’s Wort, an herbal preparation used in the treatment of depression.
J Pharmacol Exp Ther.
2000;
294
88-95
-
13
Ishihara K. et al .
Interaction of drugs and chinese herbs: pharmacokinetic changes of tolbutamide and diazepam caused by extract of Angelica dahurica
.
J Pharm Pharmacol.
2000;
52
1023-9
-
14
Venkataramanan R, Ramachandran V, Komoroski B J, Zhang S, Schiff P L, Strom S C.
Milk Thistle, a herbal supplement, decreases the activity of CYP3A4 and uridine diphosphoglucuronosyl transferase in human hepatocyte cultures.
Drug Metab Dispos.
2000;
28
1270-3
-
15
Hollander A A, Van der Woude F J, Cohen A F.
Effect of grapefruit juice on blood cyclosporine concentration.
Lancet.
1995;
346
123-4
-
16
Kantola T, Kivisto K T, Neuvonen P J.
Grapefruit juice greatly increases serum concentrations of lovastatin and lovastatin acid.
Clin Pharmacol Ther.
1998;
63
397-402
-
17
He X G, Lin L Z, Lian L Z.
Electrospray high performance liquid chromatography-mass spectrometry in phytochemical analysis of Kava (Piper methysticum) extract.
Planta Medica.
1997;
63
70-4
-
18
Gorski J C, Jones D R, Hamman M A, Wrighton S A, Hall S D.
Biotransformation of alprazolam by members of the human cytochrome P4503A subfamily.
Xenobiotica.
1999;
29
931-44
-
19
Almeida J C, Grimsley E W.
Coma from the healthfood store: interaction between kava and alprazolam.
Ann Intern Med.
1996;
125
940-1
Dr. Matthias Unger
Institute of Pharmacy and Food Chemistry
Department of Pharmaceutical Chemistry
Am Hubland
97074 Würzburg
Germany
Phone: +49 931 888 5451
Fax: +49 931 888 5494
Email: m.unger@pharmazie.uni-wuerzburg.de