Kava Fact of the Day Kava and P-glycoprotein

[The Kap'n]

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.

 

[Groggy]

To quote you and Lebot, it seems the "crude" extract by which these tests are performed are not up to par to what would be defined and know as kava. An extract, even a full spectrum extract is just that, an extract, it's not kava. So I wonder what real world impact does that make to an everyday kava drinker?

 

[The Kap'n]

To quote you and Lebot, it seems the "crude" extract by which these tests are performed are not up to par to what would be defined and know as kava. An extract, even a full spectrum extract is just that, an extract, it's not kava. So I wonder what real world impact does that make to an everyday kava drinker?

Since they tested individual kavalactones specifically, it would correspond to traditional kava consumption. The kavalactones themselves are what cause the inhibition, so at least in this instance the difference between extracts and traditional prep wouldn't be all that different in terms of the way they effect P-gp.

There doesn't seem to be any corrective mechanism in aqueous preparations that would cause a difference in P-gp inhibition over extracts. At least not yet.

 

[Alia]

Since they tested individual kavalactones specifically, it would correspond to traditional kava consumption. The kavalactones themselves are what cause the inhibition, so at least in this instance the difference between extracts and traditional prep wouldn't be all that different in terms of the way they effect P-gp.

There doesn't seem to be any corrective mechanism in aqueous preparations that would cause a difference in P-gp inhibition over extracts. At least not yet.

But wait now, if kava beverage was used rather than crude extract (and we know time and time again Lebot, Turner, others have said...*) wouldn't the "*entourage effect"
come in to play? Do extracted kavalactones behave the same as kavalactones which are "under the influence" of all the other mechanisms in kava beverage?

 

[The Kap'n]

But wait now, if kava beverage was used rather than crude extract (and we know time and time again Lebot, Turner, others have said...*) wouldn't the "*entourage effect"
come in to play? Do extracted kavalactones behave the same as kavalactones which are "under the influence" of all the other mechanisms in kava beverage?

Good question! I feel like you know more than I do about this one, though. As I'm reading, I don't see specific evidence of this in research. The entourage effect, at least our definition of it, seems to play into the way kavalactones are metabolized in the body. Individual kavalactones seem to modify the breakdown of other kavalactones.

Now that I say that, I think it would make sense that this could carry over to traditional prep. Where kavain alone metabolizes extremely fast, kavain in the presence of kavalactones such as DHM change the metabolization time. My hypothesis is this is happening due to DHM and Methysticin being present (they both have the MDP group in common, which is what gives many phytochemicals their inhibitory properties), being a substrate of CYP and P-gp, and causing the entire range of other kavalactones to be altered in terms of metabolization.

Thoughts on that? Am I on the right page, or maybe in a different ballpark?

 

[Alia]

Good question! I feel like you know more than I do about this one, though. As I'm reading, I don't see specific evidence of this in research. The entourage effect, at least our definition of it, seems to play into the way kavalactones are metabolized in the body. Individual kavalactones seem to modify the breakdown of other kavalactones.

Now that I say that, I think it would make sense that this could carry over to traditional prep. Where kavain alone metabolizes extremely fast, kavain in the presence of kavalactones such as DHM change the metabolization time. My hypothesis is this is happening due to DHM and Methysticin being present (they both have the MDP group in common, which is what gives many phytochemicals their inhibitory properties), being a substrate of CYP and P-gp, and causing the entire range of other kavalactones to be altered in terms of metabolization.

Thoughts on that? Am I on the right page, or maybe in a different ballpark?

The point I am trying to make is more a question that "needs further research".
Obviously if we are to take the entourage effect to heart, there would need to
be lots of additional, comparative research. So many of the studies for kava
and cancer prevention, Alzheimers prevention, etc. , have been done
using kava extracts. Some, indeed, with traditional beverage...but not many.
In my experience the argument I've heard from researchers is that it's easier
to use an extract (try giving a lab mouse some kava beverage). Granted, I really
doubt that the difference would be that dramatic (eg.- traditional beverage
has been shown to prevent some forms of cancer as has individual kavalactones).
But I also think it is worth the discussion and awareness of the possibility.
I go back to what Dr. Amanda Martin has said- "It's not necessarily that more
is better. [What you're looking for] is the right amount . And with kava an aqueous
solution produces the right amount." I believe the pacific island daily kava ritual
of a few cups at the end of a work day is the key. Maybe if that was practiced there
would be no need for so much perscription medications.

 

[The Kap'n]

The point I am trying to make is more a question that "needs further research".
Obviously if we are to take the entourage effect to heart, there would need to
be lots of additional, comparative research. So many of the studies for kava
and cancer prevention, Alzheimers prevention, etc. , have been done
using kava extracts. Some, indeed, with traditional beverage...but not many.
In my experience the argument I've heard from researchers is that it's easier
to use an extract (try giving a lab mouse some kava beverage). Granted, I really
doubt that the difference would be that dramatic (eg.- traditional beverage
has been shown to prevent some forms of cancer as has individual kavalactones).
But I also think it is worth the discussion and awareness of the possibility.
I go back to what Dr. Amanda Martin has said- "It's not necessarily that more
is better. [What you're looking for] is the right amount . And with kava an aqueous
solution produces the right amount." I believe the pacific island daily kava ritual
of a few cups at the end of a work day is the key. Maybe if that was practiced there
would be no need for so much perscription medications.

Ohh I see what you're saying. I think there's still plenty of room for further research because it seems the bulk of what I'm reading always states something to the effect that they acknowledge that the results may not translate into real world information. I like the way Aporosa's papers go in regards to how they generally focus on traditional drinking instead of extract studies.

 

[Alia]

Ohh I see what you're saying. I think there's still plenty of room for further research because it seems the bulk of what I'm reading always states something to the effect that they acknowledge that the results may not translate into real world information. I like the way Aporosa's papers go in regards to how they generally focus on traditional drinking instead of extract studies.

Both Apo Aporosa and Jerome Sarris lean towards the aqueous/traditional beverage .