Misc Kratom and Truvada

[Twisted_Chemist]

Wasnt sure if this went here or in advanced drug, move if wrong and I apologize.


I just got my prescription for truvada (emtricitabine/tenofovir disoproxil fumarate). I've searched around to try and figure it out, but truvada still does not have a interactions list that's complete. Any personal reaction would be greatly appreciated.

Mechanism of ActionEmtricitabine:

Emtricitabine, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of the HIV-1 reverse transcriptase (RT) by competing with the natural substratedeoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5′-triphosphate is a weak inhibitor of mammalian DNA polymerase α, β, ε and mitochondrial DNA polymerase γ.

Tenofovir disoproxil fumarate: Tenofovir disoproxil fumarate is an acyclic nucleosidephosphonate diester analog of adenosine monophosphate. Tenofovir disoproxil fumarate requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylationsby cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activityof HIV-1 RT by competing with the natural substrate deoxyadenosine 5′-triphosphate and,after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weakinhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ.


Pharmacokinetics


One TRUVADA Tablet was bioequivalent to one EMTRIVA Capsule (200 mg)plus one VIREAD Tablet (300 mg) following single-dose administration to fasting healthysubjects (N=39).

Emtricitabine: The pharmacokinetic properties of emtricitabine are summarized in Table 1.Following oral administration of EMTRIVA, emtricitabine is rapidly absorbed with peak plasma concentrations occurring at 1?2 hours post-dose. In vitro binding of emtricitabine to human plasma proteins is <4% and is independent of concentration over the range of 0.02−200 ?g/mL. Following administration of radio labelled emtricitabine, approximately 86%is recovered in the urine and 13% is recovered as metabolites. The metabolites of emtricitabine include 3′-sulfoxide diastereomers and their glucuronic acid conjugate. Emtricitabine is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of EMTRIVA, the plasma emtricitabine half-life is approximately 10 hours. Has No CYP interaction

Tenofovir disoproxil fumarate: The pharmacokinetic properties of tenofovir disoproxil fumarate are summarized in Table 1. Following oral administration of VIREAD, maximum tenofovir serum concentrations are achieved in 1.0 - 0.4 hour. In vitro binding of tenofovir to human plasma proteins is <0.7% and is independent of concentration over the range of 0.01?25 ?g/mL. Approximately 70?80% of the intravenous dose of tenofovir is recovered as unchanged drug in the urine. Tenofovir is eliminated by a combination of glomerular filtrationand active tubular secretion. Following a single oral dose of VIREAD, the terminal eliminationhalf-life of tenofovir is approximately 17 hours.

Tenofovir disoproxil is a prodrug that is quickly absorbed from the gut and cleaved to release tenofovir.[7] Inside cells, tenofovir is phosphorylated to tenofovir diphosphate (which is actually a triphosphate, as tenofovir itself already has one phosphate residue), the active compound that inhibits reverse transcriptase via chain termination.


In fasting persons, bioavailability is 25%, and highest blood plasma concentrations are reached after one hour.[13] When taken with fatty food, highest plasma concentrations are reached after two hours, and the area under the curve is increased by 40%.[13] It has no significant interactions with cytochrome P450 enzymes.


Tenofovir is mainly excreted via the kidneys, both by glomerular filtration and by tubular secretion using the transport proteins OAT1, OAT3 and ABCC4.


If you CL rate or anything from chart let me know. It is also in FDA Document NDA 21-752/S-005

From what I can tell their should not be any interactions, but better safe than sorry. And above an an abridged summery of the drugs, for full text see each individual drug. Only thing im worried about is the combo is boxing my kidneys or liver.


Thanks,

The Twisted Chemist

 

[Scrofula]

Pretty sure it's been approved for a long time. But you want to know if it's safe with kratom?

Problem is, there won't be any list of interactions for kratom, since there hasn't been a single clinical study on it as of the beginning of the year (there will be group interactions, eg. downer + downer = bad).

Truvada is a descendent of AZT, not a gentle, friendly class of drugs; but, it is prophylaxis. I figure risky sex every night, night after night, isn't the sort of style Truvada users would dress for. And then it wouldn't be prophylaxis anymore.

Point being even if there was risk, you don't take it every day. But good luck even finding out all the active compounds in kratom to know. It's not something I'd worry much about, though.

 

[Twisted_Chemist]

First Thanks for your reply!

You do take it everyday (When you dont its up to 30% effective or something like that). Studies show that taking it every day is the only way to get that 90% immunity and yes I know Truvada is a approved but their have been no drug interaction trials since its a real small percentage of people who take it, meaning their is no data on what it may or may not react with at all except the ones that have been reported. But as word of mouth is the least reliable form of reporting to drug companies I dont really count that as accurate data. To many variables as you cant ask question to follow up to make sure you definition of a symptom is the same as theirs.

What I am mostly looking for is other peoples first hand reports, that way if I have any questions I can ask specific question in either PM or on the board. I for the most part I understand the pharmacokinetics and pharmacodynamics.

To me that there is no CYP interaction on Emtricitabine but I cant find out if there is any other P450 enzymes that interact with it. Tenofovir states it has very little action with the P450's enzyme, but not what enzymes it does interact with. For the most part i think the liver is not the problem but the kidney could be.

Since they both put the kidneys^{1}{2) under strain, im worried if it could be to much to take both together. Like I said I would love any feedback anyone has from personal experience or any input on your thoughts, please back up theories if you have one (I.E. I think this because NOT just do it its safe.)

Also, just an fyi, its really bad to stereotype things your not familiar with. Its not just for people who want to have unsafe sex, in fact if you take it correctly its only 90% effective and your still supposed to wear a condom. Its for any high risk group for exposure. Such as (but not limited to) people who work with patients that are HIV+ or have AIDS and have high risk of exposure from handling blood or other bodily fluids. Its also prescribed to IV drug users (In my state at least) if they ask for it and it also helps treat the HIV infection.

Maybe this should be moved to ADD?

 

[Scrofula]

I haven't stereotyped anything, other than marketing logic. Considering I've been exposed repeatedly to more live virus than all the IV users in a major city put together, over their lifetimes, I'd include myself in that list.

Now, I don't know why the interest in cytrochrome P450 enzymes exactly. It's true they can screw with drug metabolism. One thing to look at with Truvada is the resemblance to nucleotides. Emtriva looks like a pyrimidine nucleoside, just with a fluorine in the base and a sulfur in the "sugar". Tenofovir is adenine, just with a fucked-up phosphate ester.

So your body will treat them like indigestible nucleosides and nucleotides. You don't normally use CYP P450s to break down those things. They get fed into the uric acid cycle. If that can't happen because of annoying substitutions, my guess is glucuronidation and your kidneys still take care of it.

I have no idea about a substance like mitragynine; all I know is it resembles yohimbine, and has a beta-carboline hidden in the structure.

So, I think cytochrome involvement isn't the biggest worry.

But I don't have a lot of confidence in all the sources out there, since the internet refs mention HBV repeatedly. HBV is a DNA virus, and doesn't need reverse transcriptase. At least not to clone its genome. (It's DNA genome does make it delightful to work with, but also lets it survive in the open air for quite a long time.)

Thinking of things that might interfere with purine metabolism: caffeine, and theobromine from chocolate. For some reason I'm remembering mushrooms, but it couldn't be for the chitin.

Gout medicine? Uloric, colchicine.

 

[Twisted_Chemist]

Thanks again for the reply.

Like stated not to worried about the liver, was mostly worried about interactions talking them together could either cause an increse or decrese in blood level serums of any of the three drugs.

With the kidneys im a little more worried about. From the studies ive seen:

1) Overall, creatinine clearance decreased slightly after starting Truvada, by an average of 2.5% over 18 months. There was a consistent relationship between eGFR decline and increasing levels of tenofovir or emtricitabine in hair samples: eGFR fell by 5.6% among people with the highest quartile of hair drug levels (indicating daily dosing).

Older people were more likely to experience a clinically significant decrease (i.e., have their eGFR fall below 70 mL/min). About a quarter of people over age 50 with high drug levels fell below this threshold, but among participants under age 40 the proportion never rose above 5% even with daily dosing. People with slightly low eGFR at baseline (less than 90 mL/min) were also more likely to fall below the threshold.

2)Albert Liu, MD, from the San Francisco Department of Public Health presented a similar analysis of kidney function among participants in the PrEP Demo Project, which enrolled more than 500 gay and bisexual men and transgender women. All participants received once-daily Truvada PrEP on an open-label basis for a year.

In this study, the metabolized form of tenofovir was measured in dried blood spots from a subset of participants; 82% had drug levels suggesting they took at least four Truvada doses a week.

Overall, eGFR decreased by an average of 2.8% from baseline to week 12?similar to the decline in the iPrEx analysis?and then remained stable through the end of the study. Just 11 people (2.4%) saw their creatinine clearance fall by 10% or more.

Again, larger declines in eGFR were associated with higher tenofovir levels, older age, and lower eGFR at baseline. About a third of people older than 45 who started with an eGFR less than 90 mL/min fell below 70 mL/min after starting Truvada. But among people who started with 90 mL/min or higher, less than 5% fell below the threshold regardless of age.

And the third study done at my work

3) Kenneth Mugwanya from the University of Washington in Seattle presented findings on more serious kidney damage in over 1,500 participants in the Partners PrEP trial, which compared Truvada, tenofovir alone, and placebo for HIV-negative partners in serodiscordant heterosexual couples in Africa.

Proximal tubulopathy was rarely seen: 1.7% (13 people) in the Truvada arm and 1.3% (10 people) in the placebo arm, which was not a significant difference. The study also showed that people who experienced a steep decline in eGFR were not necessarily more likely to develop tubulopathy.


So from this I assume that truvada by itself is relativly safe but when you add the effects of kratom on the kidneys (see annotation note one in post above) im not sure what the outcome is. Again looking mostly for first had experiences, but any input is appreciated.

And yes you will see lots of info about hep b with tenofovir as it can treat/partially treat it. Taking truvada with undiagonosed hep b can lead to making hep b harder to treat

 

[Twisted_Chemist]

Kratom and truvada interactions

I am looking for interactions on the combo mainly in the kidneys.

With the the liver I was mostly worried about interactions when taking them together that could either cause a serum increase or decrees in blood level between any of any of the three drugs.

It's the kidneys im most worried about. From the studies ive seen:

1) Overall, creatinine clearance decreased slightly after starting Truvada, by an average of 2.5% over 18 months. There was a consistent relationship between eGFR decline and increasing levels of tenofovir or emtricitabine in hair samples: eGFR fell by 5.6% among people with the highest quartile of hair drug levels (indicating daily dosing).

Older people were more likely to experience a clinically significant decrease (i.e., have their eGFR fall below 70 mL/min). About a quarter of people over age 50 with high drug levels fell below this threshold, but among participants under age 40 the proportion never rose above 5% even with daily dosing. People with slightly low eGFR at baseline (less than 90 mL/min) were also more likely to fall below the threshold.

2)Albert Liu, MD, from the San Francisco Department of Public Health presented a similar analysis of kidney function among participants in the PrEP Demo Project, which enrolled more than 500 gay and bisexual men and transgender women. All participants received once-daily Truvada PrEP on an open-label basis for a year.

In this study, the metabolized form of tenofovir was measured in dried blood spots from a subset of participants; 82% had drug levels suggesting they took at least four Truvada doses a week.

Overall, eGFR decreased by an average of 2.8% from baseline to week 12?similar to the decline in the iPrEx analysis?and then remained stable through the end of the study. Just 11 people (2.4%) saw their creatinine clearance fall by 10% or more.

Again, larger declines in eGFR were associated with higher tenofovir levels, older age, and lower eGFR at baseline. About a third of people older than 45 who started with an eGFR less than 90 mL/min fell below 70 mL/min after starting Truvada. But among people who started with 90 mL/min or higher, less than 5% fell below the threshold regardless of age.

And the third study at the lab I work

3) Kenneth Mugwanya from the University of Washington in Seattle presented findings on more serious kidney damage in over 1,500 participants in the Partners PrEP trial, which compared Truvada, tenofovir alone, and placebo for HIV-negative partners in serodiscordant heterosexual couples in Africa.

Proximal tubulopathy was rarely seen: 1.7% (13 people) in the Truvada arm and 1.3% (10 people) in the placebo arm, which was not a significant difference. The study also showed that people who experienced a steep decline in eGFR were not necessarily more likely to develop tubulopathy.


So from this I assume that truvada by itself is relativly safe but when you add the effects of kratom on the kidneys (will link study again once i find it, but its called kidney impariment by the three k's and is on pubmed, i think) im not sure what the outcome is. Again looking mostly for first had experiences, but any input is appreciated.

I am a chronic pain patiant who relys on my kratom.

 

[Tubbs]

Are you on mobile? If you are you can't edit your post from the mobile site, it just deletes them.

Because it's listed as you deleted it.

 

[Twisted_Chemist]

Ah i was wondering if my phone had something to do with it after I posted that. Thanks for the clarification.

 

[Tubbs]

Not a problem man, your question is out of my realm of expertise, but I hope you get the answers you're looking for.

 

[falsifiedhypothesi]

You might be better off doing some in depth research on your own for this kinda thing. Sounds like you already have done research but as far as i know there hasn?t been a lot of studies on kratom. It?s safety has been proven through centuries of use by humans but i believe the scientific research has only just begun.

 

[T. Calderone]

^ Exactly. The trouble is, since kratom is not a pharmaceutical drug there is no database to check for possible interactions.

 

[Scrofula]

Not sure why you chose to delete this.

This info is kind of important for a site intended for harm reduction, on a forum intended to provide safe practice guidelines for IV drug users. They are at highest risk for HIV and hepatitis transmission; many of them use kratom between more typical drug IV sessions. I think that risk doesn't get hardly any mention around here, TBH.

Considering many at risk populations, including burned-out former corporate researchers-turned unemployed internet forum mods, are downright fans of illicit drug use, that kind of interaction data would be nice to have for all the usual comorbidities.

I have mixed feelings about this "prophylaxis" but IV drug users should know its an option.

The numbers you gave are clinical, which is always better than test tube affinity, and seem to show a pretty safe drug, at least for your kidneys. We could use more, so I think this should stay up.

Nothing, though, is better than mod speculation, and I speculate any interactions won't be mediated through cytochrome induction or inhibition.

 

[Twisted_Chemist]

Yeah the kratom research I found is this one: Hepatotoxicity Induced by ?the 3Ks?: Kava, Kratom and Khat

And can be found at
https://www.ncbi.nlm.nih.gov

It is behind a paywall but is a good read.

Also bought this on google play for 50% off.

Kratom and Other Mitragynines

But between the two im still not to sure if its safe or not. Because like you said it hasnt been through any clinical trails.

 

[falsifiedhypothesi]

You should try contacting professionals/professors that work/study in this field. Although i wouldn?t take the word of an authority as gospel they might provide valuable in-site and come to a well thought out solution to your question.

The shit reality is that we won?t really know until there are more studies. That being said i hope someone can provide you with valuable information.

 

[Twisted_Chemist]

First thanks everyone for your replies.

I asked a fellow in nephrology at the lab I work in who also uses kratom, but he basically shrugged saying its to early to tell for both since neither have a had drug interaction trials. Truvada since its a really small population who takes it, their isn't a pool large enough to draw any conclusions and kratom well its kratom so yeah.

 

[Twisted_Chemist]

I hope this isnt considered self bumping as this has nothing to do with my last post at all. If it is I apologize and you can smack me.

I found this on a website, and not to sure about its accuracy

Role of liver in Kratom metabolism

The function of the liver is detoxification of the blood, converting the nutrients into useful forms and also metabolizing the toxic substances. It does so with the help of certain microsomal enzymes. Kratom is metabolized by the cytochrome p450 system of the liver.
If Kratom is taken in regular doses, it won’t harm the hepatocytes, however larger amounts of Kratom increases the workload load of hepatocytes, this is where the cells fell, and liver toxicity occurs. If the [site this linked to had anything other then kratom for sale, the English was so bad I wouldn't know] is reduced, these liver cells start functioning properly. Kratom doesn’t cause liver cirrhosis.
Kratom abuse can cause intrahepatic cholestasis. In this liver disease, there is the abnormal release of bile. However, it is a very rare condition that occurs in Kratom users. It only happens if you have other co-morbidities like hepatitis etc.
On biopsy of the liver, it is seen that the there is a pattern of drug-induced cholestatic injury. The user usually complains of pain on the right side of the upper abdomen. The liver is enlarged and tender. Liver function tests show elevated levels of enzymes especially ALT. The person complains of dark urine, yellowing of skin, nausea, and pain.
The onset of injury is usually within 2 to 8 weeks of Kratom abuse. The user shows symptoms of fatigue, pruritus and dark urine followed by jaundice. Serum bilirubin levels may rise above 20mg/dL. It can be accompanied by acute renal failure and bone marrow toxicity. The disease can be prolonged, but it resolves spontaneously when the dose of Kratom is tapered off.

(I have never seen any reports of this. Going to search for it later in library at work.)

Role of kidneys in Kratom excretion

Kratom is responsible for increasing the urinary output the way coffee does. Extensive research shows that Kratom doesn’t cause injury to the renal system. It only causes acute renal failure in very rare cases when the serum bilirubin level is highly raised. According to users, they haven’t experienced any sort of kidney problem. Kidney stone formation due to Kratom intake is a myth.

(Again havn't heard this about kidney stones so again I question the source the author got their materials from)

 

[Scrofula]

I'm a little concerned with your careful editing, OP. You left out the part where the NLM's livertox blurb says "Chronic use of kratom recreationally has been associated with rare instances of acute liver injury."

I mean, it starts the paragraph you took the "2-8 weeks" line from, the one you directly linked to. Why would you leave an important qualifier like that out? You were the one concerned about Truvada disrupting your kratom use; this sounds like some scare-trolling, if it wasn't for the "washing the apartment" kratom brochure in your first link.

 

[Twisted_Chemist]

Thanks guys for all your input. I talked to a clinical pharmacologist (sp) and they said the only thing to watch for is other drugs that hurt the kidney's , such as ib or naproxon. They said most of the people who take truvada and nsaids are the ones who end up in trouble.

They also said they dont worry about the same problems with the liver since their is very little interaction their.

As i find out more ill post.

Again, thanks everyone for your input and replies

 

[Twisted_Chemist]

I'm a little concerned with your careful editing, OP. You left out the part where the NLM's livertox blurb says "Chronic use of kratom recreationally has been associated with rare instances of acute liver injury."

I mean, it starts the paragraph you took the "2-8 weeks" line from, the one you directly linked to. Why would you leave an important qualifier like that out? You were the one concerned about Truvada disrupting your kratom use; this sounds like some scare-trolling, if it wasn't for the "washing the apartment" kratom brochure in your first link.

Not sure what post i put it in, but tje liver isnt something im to worried about only the kidney interaction between the two. Truvada has almost nill interaction with the liver.

I apologize if you think i left something out important.

 

[Twisted_Chemist]

Just found this Looks like no, metabolism happens mainly in the liver.

https://doi.org/10.2147/DDDT.S79658

"...urine excretion of the unchanged mitragynine form was as low as 0.14%, this suggests that renal excretion should not be a significant route of excretion, even when its bioavailability was taken into account. Based on our findings, we propose that mitragynine is mainly metabolized by hepatic metabolism to other metabolites."

Edit: cleaned up URL to the study