cactus
Frequent Contributor (1K+ posts)
Member # 7347
posted
Does anyone know what detox pathway artmesinin uses in the liver?
Is it the same one used by Rifampin?
Thx.
-------------------- �Did you ever stop to think, and forget to start again?� - A.A. Milne Posts: 1987 | From No. VA | Registered: May 2005
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Keebler
Honored Contributor (25K+ posts)
Member # 12673
posted
-
It does use the Cytochrome P-450 pathway. Within that, I'm not sure.
I'll come back and post what I found when looking at this earlier as I have trouble with the C P-450 pathway.
Mol Pharmacol. 2005 Jun;67(6):1954-65. Epub 2005 Mar 10. Links
Antimalarial artemisinin drugs induce cytochrome P450 and MDR1 expression by activation of xenosensors pregnane X receptor and constitutive androstane receptor.
Burk O, Arnold KA, Nussler AK, Schaeffeler E, Efimova E, Avery BA, Avery MA, Fromm MF, Eichelbaum M.
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstrasse 112, D-70376 Stuttgart, Germany. [email protected]
Artemisinin drugs are of utmost importance in the treatment of malaria, because they represent the sole class of therapeutically used antimalarial drugs to which malaria parasites have not yet developed resistance.
The major disadvantage of these medicines is the comparatively high recrudescence rate, which has been attributed to the remarkable decrease of artemisinin plasma concentrations during multiple dosing.
Autoinduction of CYP2B6-mediated metabolism has been implicated as the underlying mechanism. So far, the molecular mechanism of induction by artemisinin has not been resolved.
Because the xenosensors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) have been shown to mediate induction of drug-metabolizing enzymes and drug transporters, we investigated the hypothesis that artemisinin induces cytochrome P450 expression by activating PXR and/or CAR.
By combining in vitro transfection methods and quantitative analyses of gene expression in cell lines and primary human hepatocytes,
we here show that artemisinin drugs activate human PXR as well as human and mouse CAR and induce the expression of CYP2B6, CYP3A4, and MDR1 in primary human hepatocytes and in the human intestinal cell line LS174T.
Furthermore, we demonstrate that artemisinin acts as a ligand of both nuclear receptors, because it modulates the interaction of the receptors with coregulators.
In conclusion, activation of PXR and CAR and especially the resulting induction of CYP3A4 and MDR1 demonstrate that artemisinin has a higher risk of potential drug interactions than anticipated previously.
cactus
Frequent Contributor (1K+ posts)
Member # 7347
posted
Thanks, Keebler. That's exactly what I needed to know.
-------------------- �Did you ever stop to think, and forget to start again?� - A.A. Milne Posts: 1987 | From No. VA | Registered: May 2005
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posted
help me here... does that mean that artemisinin should not be taken when you are taking rifamprin?
Posts: 758 | From now TX | Registered: Mar 2001
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cactus
Frequent Contributor (1K+ posts)
Member # 7347
posted
mjbucuk, I would follow your LLMD's suggestions on that one.
Some people genetically lack the necessary detox pathway in the liver to safely detox Rifampin.
I think Artemisinin uses the same detox pathway - so if someone cannot detox Rifampin, I would think they would have trouble with artemisinin as well.
If you're taking Rifampin already, my guess is that you're okay.
If you lacked the detox pathway, you wouldn't be able to be on Rifampin for long without a trip to the ER (speaking from personal experience here, unfortunately).
Hope that helps.
-------------------- �Did you ever stop to think, and forget to start again?� - A.A. Milne Posts: 1987 | From No. VA | Registered: May 2005
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Rianna
Frequent Contributor (1K+ posts)
Member # 11038
posted
Cool post..........
So can you check if the Cytochrome P-450 pathway is compramised in some patients?
What are the signs if you cannot detox art through this pathway - is it elavated LFT's?
Can you improve the detox of this pathway?
I know most LLMD's cycle patients on and off art (mine does 3 days on 11 days off) and I assume thats due to stopping drug resistance and just in case this pathway is compramised?
Rianna
[ 13. December 2008, 06:15 AM: Message edited by: Rianna ]
Posts: 1172 | From UK | Registered: Jan 2007
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