Kavas Interaction at P-Glycoprotein
Today’s fact of the day deals with a mechanism of metabolism and distribution known as P-glycoprotein. P-glycoprotein is involved in the absorption, distribution, and excretion of many drugs (Teschke 2010). In the liver P-gp pumps toxins into the bile ducts to be excreted. P-gp exists in animals, fungi, and bacteria where it likely evolved as a defense mechanism against harmful substances found in nature (Wikipedia contributors 2021). P-glycoprotein also protects the brain from harmful substances by preventing them from entering through the blood brain barrier. (Aryal et al. 2017)
In 2005 a study was performed looking into the possibility of kavalactones from kava to interfere with P-gp functions. This was done to see whether they could discover if kava was responsible with what are called “herb-drug” interactions, or interactions between an herbal product and pharmaceutical product. A crude extract was used as well as individual kavalactones. Crude in this context refers to a full spectrum extract instead of targeting the individual kavalactones (“Extract” n.d.). 100% of the kava extract products on the market are “crude extracts” by this definition.
Kava was tested against known P-gp inhibitors namely Verapamil, and Quinidine and it was found that kavalactones, some more than others, were able to inhibit P-gp in a concentration dependent manner. The results of the study show that kavalactones can be divided into distinct groups based on their inhibition profile. Kavain/DHK were the lowest inhibiting KLs followed by methysticin and DHM, and finally by desmethoxyyangonin and yangonin for the highest inhibitory activities (Weiss et al. 2005).
What does this mean to the daily kava drinker? Sustained inhibition of P-gp may cause drugs to metabolize at a slower rate. This is similar to the fact of the day on CYP450 enzyme inhibition. Kava theoretically in this context can cause a drug to stay in your system for longer periods of time. Typically the inhibition is seen with an overlap of substances that inhibit CYP3A4 (Yasuda et al. 2002). This means that the grapefruit warning on medications should be satisfactory to avoid any interaction with prescription medications, P-gp, and kava (Eagling, Profit, and Back 1999). The study of P-gp inhibition is an important topic of research regarding various drug resistant cancers and may help open the door to more effective therapies, as well as formation of new drugs which may not be bioavailable under normal conditions.
Aryal, Muna, Krisztina Fischer, Caroline Gentile, Salvatore Gitto, Yong-Zhi Zhang, and Nathan McDannold. 2017. “Effects on P-Glycoprotein Expression after Blood-Brain Barrier Disruption Using Focused Ultrasound and Microbubbles.” PloS One 12 (1): e0166061.
Eagling, V. A., L. Profit, and D. J. Back. 1999. “Inhibition of the CYP3A4-Mediated Metabolism and P-Glycoprotein-Mediated Transport of the HIV-1 Protease Inhibitor Saquinavir by Grapefruit Juice Components.” British Journal of Clinical Pharmacology 48 (4): 543–52.
“Extract.” n.d. Accessed April 13, 2021. https://medical-dictionary.thefreedictionary.com/crude+extract.
Teschke, Rolf. 2010. “Kava Hepatotoxicity: Pathogenetic Aspects and Prospective Considerations.” Liver International: Official Journal of the International Association for the Study of the Liver 30 (9): 1270–79.
Weiss, Johanna, Alexandra Sauer, Andreas Frank, and Matthias Unger. 2005. “Extracts and Kavalactones of Piper Methysticum G. Forst (kava-Kava) Inhibit P-Glycoprotein in Vitro.” Drug Metabolism and Disposition: The Biological Fate of Chemicals 33 (11): 1580–83.
Wikipedia contributors. 2021. “P-Glycoprotein.” Wikipedia, The Free Encyclopedia. January 18, 2021. https://en.wikipedia.org/w/index.php?title=P-glycoprotein&oldid=1001198583.
Yasuda, Kazuto, Lu-Bin Lan, Dominique Sanglard, Katryn Furuya, John D. Schuetz, and Erin G. Schuetz. 2002. “Interaction of Cytochrome P450 3A Inhibitors with P-Glycoprotein.” The Journal of Pharmacology and Experimental Therapeutics 303 (1): 323–32.
Today’s fact of the day deals with a mechanism of metabolism and distribution known as P-glycoprotein. P-glycoprotein is involved in the absorption, distribution, and excretion of many drugs (Teschke 2010). In the liver P-gp pumps toxins into the bile ducts to be excreted. P-gp exists in animals, fungi, and bacteria where it likely evolved as a defense mechanism against harmful substances found in nature (Wikipedia contributors 2021). P-glycoprotein also protects the brain from harmful substances by preventing them from entering through the blood brain barrier. (Aryal et al. 2017)
In 2005 a study was performed looking into the possibility of kavalactones from kava to interfere with P-gp functions. This was done to see whether they could discover if kava was responsible with what are called “herb-drug” interactions, or interactions between an herbal product and pharmaceutical product. A crude extract was used as well as individual kavalactones. Crude in this context refers to a full spectrum extract instead of targeting the individual kavalactones (“Extract” n.d.). 100% of the kava extract products on the market are “crude extracts” by this definition.
Kava was tested against known P-gp inhibitors namely Verapamil, and Quinidine and it was found that kavalactones, some more than others, were able to inhibit P-gp in a concentration dependent manner. The results of the study show that kavalactones can be divided into distinct groups based on their inhibition profile. Kavain/DHK were the lowest inhibiting KLs followed by methysticin and DHM, and finally by desmethoxyyangonin and yangonin for the highest inhibitory activities (Weiss et al. 2005).
What does this mean to the daily kava drinker? Sustained inhibition of P-gp may cause drugs to metabolize at a slower rate. This is similar to the fact of the day on CYP450 enzyme inhibition. Kava theoretically in this context can cause a drug to stay in your system for longer periods of time. Typically the inhibition is seen with an overlap of substances that inhibit CYP3A4 (Yasuda et al. 2002). This means that the grapefruit warning on medications should be satisfactory to avoid any interaction with prescription medications, P-gp, and kava (Eagling, Profit, and Back 1999). The study of P-gp inhibition is an important topic of research regarding various drug resistant cancers and may help open the door to more effective therapies, as well as formation of new drugs which may not be bioavailable under normal conditions.
Aryal, Muna, Krisztina Fischer, Caroline Gentile, Salvatore Gitto, Yong-Zhi Zhang, and Nathan McDannold. 2017. “Effects on P-Glycoprotein Expression after Blood-Brain Barrier Disruption Using Focused Ultrasound and Microbubbles.” PloS One 12 (1): e0166061.
Eagling, V. A., L. Profit, and D. J. Back. 1999. “Inhibition of the CYP3A4-Mediated Metabolism and P-Glycoprotein-Mediated Transport of the HIV-1 Protease Inhibitor Saquinavir by Grapefruit Juice Components.” British Journal of Clinical Pharmacology 48 (4): 543–52.
“Extract.” n.d. Accessed April 13, 2021. https://medical-dictionary.thefreedictionary.com/crude+extract.
Teschke, Rolf. 2010. “Kava Hepatotoxicity: Pathogenetic Aspects and Prospective Considerations.” Liver International: Official Journal of the International Association for the Study of the Liver 30 (9): 1270–79.
Weiss, Johanna, Alexandra Sauer, Andreas Frank, and Matthias Unger. 2005. “Extracts and Kavalactones of Piper Methysticum G. Forst (kava-Kava) Inhibit P-Glycoprotein in Vitro.” Drug Metabolism and Disposition: The Biological Fate of Chemicals 33 (11): 1580–83.
Wikipedia contributors. 2021. “P-Glycoprotein.” Wikipedia, The Free Encyclopedia. January 18, 2021. https://en.wikipedia.org/w/index.php?title=P-glycoprotein&oldid=1001198583.
Yasuda, Kazuto, Lu-Bin Lan, Dominique Sanglard, Katryn Furuya, John D. Schuetz, and Erin G. Schuetz. 2002. “Interaction of Cytochrome P450 3A Inhibitors with P-Glycoprotein.” The Journal of Pharmacology and Experimental Therapeutics 303 (1): 323–32.
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