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Traditional aqueous kava extracts inhibit CYP4501A2 in humans
Author(s) -
Russmann S.,
Barguil Y.,
Wenk M.,
Theurillat R.,
Cabalion P.,
Choblet E.,
Rentsch K.,
Lauterburg B. H.
Publication year - 2004
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2003.11.317
Subject(s) - chlorzoxazone , kava , mephenytoin , paraxanthine , debrisoquine , caffeine , chemistry , cyp1a2 , pharmacology , cyp2d6 , cyp3a4 , cyp2e1 , cyp2c19 , cytochrome p450 , medicine , biochemistry , metabolism
Purpose Consumption of traditional aqueous kava (Piper methysticum Forst. f.) extracts is common in the Pacific region, whereas commercial products have been withdrawn in many countries due to rare but severe hepatotoxicity. Previous in‐vitro studies suggest that kavalactones are metabolized via CYP450 and that they have an inhibitory effect on these enzymes, which may be relevant for interactions as well as for the mechanism by which kava rarely causes hepatotoxicity. Methods: In a cross‐over study, 6 healthy chronic kava consumers from New Caledonia (estimated intake of kavalactones 7–27 grams per week for >6 years) received probe‐drug cocktails on two consecutive days. After complete stop of kava drinking for 4 weeks they received the same probe‐drugs again. Phenotypic trait measurements were determined for the metabolizing CYP450 enzymes at both time points. Results: Serum concentration ratios with and without kava exposure for paraxanthine/caffeine (CYP1A2) were 0.3±0.1 vs. 0.6±0.2 (mean±SD, p=0.02), for 1‐OH‐midazolam/midazolam (CYP3A4) 0.4±0.1 vs. 0.4±0.2 (p=0.75), and for 6‐OH‐chlorzoxazone/chlorzoxazone (CYP2E1) 0.9±0.6 vs. 1.4±1.1 (p=0.16). Urinary recovery ratios for debrisoquine/OH‐debrisoquine (CYP2D6) were 0.8±0.4 vs. 0.8±0.6 (p=0.82) and for mephenytoin/4‐OH‐mephenytoin (CYP2C19) 2.0±0.9 vs. 1.5±0.6 (p=0.29). Conclusion: Traditional kava drinking in high amounts inhibits CYP1A2, but does not affect CYP2D6, CYP2C19, CYP2E1 or CYP3A4 activities. Clinical Pharmacology & Therapeutics (2004) 75 , P83–P83; doi: 10.1016/j.clpt.2003.11.317