Benzos Confused with different claims about what CYP Liver Enzymes Inhibit Clonazepam?

[Thomas29]

To My knowledge Clonazepam has only CYP3A4 And CYP2D6 to Inhibit it. But in the Benzo Megathread it lists CYP3A4 as a minor amount metabolized when compared to the amount that CYP2C19 Metabolizes which I can not find anywhere through A Google search saying anything about CYP2C19 Inhibiting Clonazepam at all?


The Benzo Megathread also did not even mention CYP2D6 at all which I thought was odd.

 

[Thomas29]

Should I post this in another Thread with less Traffic So it will be Read And Noticed unlike with all the constant New Posts in Other Drugs Sub-Forum?

 

[Lorne???]

It is primarily 3A4, because it is far more abundant in the human body than 2C19

2C19 DOES metabolize, just to a lesser extent

2D isn’t involved significantly

So inhibit 3A4, w grapefruit juice inhibits both 3a4 and 2C19

Hope that helps

 

[Thomas29]

It is primarily 3A4, because it is far more abundant in the human body than 2C19

2C19 DOES metabolize, just to a lesser extent

2D isn’t involved significantly

So inhibit 3A4, w grapefruit juice inhibits both 3a4 and 2C19

Hope that helps

Thank You that was extremely helpful especially the Fact about Grapefruit juice Inhibiting 2C19 I never knew that. I haven't come across anything mentioning the Inhibition of that Liver Enzyme only CYP3A4 And another Liver Enzymes but it is such weak inhibition it did not matter.


How strongly does Grapefruit Juice Inhibit CYP2C19 is it as strongly as it Inhibits CYP3A4?

 

[apocalypse_when]

Thank You that was extremely helpful especially the Fact about Grapefruit juice Inhibiting 2C19 I never knew that. I haven't come across anything mentioning the Inhibition of that Liver Enzyme only CYP3A4 And another Liver Enzymes but it is such weak inhibition it did not matter.


How strongly does Grapefruit Juice Inhibit CYP2C19 is it as strongly as it Inhibits CYP3A4?

Im sure you already know this but it has to be the "pure" white grapefruit juice and not the concentrate. I find that 500-750ml of the Tropicana Pure White Grapefruit Juice works great for this and for loperamide.

1 litre would be better but not significantly and drinking a full litre is a bit hard for many as it doesn't taste great...

 

[Lorne???]

It doesn?t have to be white. Different strands inhibit differently. White or mixed would be fine, try to down a liter with 409-809 mg cimetidine

Good luck

 

[apocalypse_when]

It doesn?t have to be white. Different strands inhibit differently. White or mixed would be fine, try to down a liter with 409-809 mg cimetidine

Good luck

Thats interesting as I've read different things, some studies say just white snd some say white or ruby (but must be the pure and not concentrate for all types). What's the different enzymes for each one?

 

[Thomas29]

I Am using Tropicana's Ruby Red Grapefruit Juice nothing Added And Nothing taken away is what it says on the back And it is Not from Concentrate But I have Read Grapefruit DOES NOT Inhibit CYP2C19 can you Reference any Studies for Me Please?

 

[Speed King]

white grapefruit juice works to a point. Its like a drug, you have to cycle it.

 

[Thomas29]

^ What you mean cycle? Due to tolerance development? I Am not worried about Tolerance I Am worried about how Long I can go between Re-Dosing since I Am trying to Lower My Dose not to be confused with stopping My use completely. I Read Grapefruit Juice starts to have Inhibiting Effect decline 5 Hours after last "use" with 72-96 Hours for the Inhibiting Effect to Fully wear off.


I can not find anything on Google claiming that Grapefruit Juice Inhibits CYP2C19 just CYP3A4 And only High Concentrations of Grapefruit Juice used ideally 3x 200ML "Uses" Daily for Liver Inhibiting Effect And that Grapefruit mostly/only just Inhibits the Intestinal Tract And is Good for Oral use of Xanax But I Read in A Post someone having the Theory that Clonazepam is Inhibited in the Liver And not anywhere else which is only A theory keep in mind.


But the ONLY IMPORTANT QUESTION I have is does Grapefruit have ANY concrete evidence of CYP2C19 Inhibiting Effect AT ALL?

 

[Jekyl Anhydride]

Thats interesting as I've read different things, some studies say just white snd some say white or ruby (but must be the pure and not concentrate for all types). What's the different enzymes for each one?

White and colored grapefruit juice produce similar pharmacokinetic interactions
We measured concentrations of three major furanocoumarin derivatives, bergaptol, bergamottin, and 6',7'-dihydroxybergamottin, with high-performance liquid chromatography in 21 brands of grapefruit juice sold in Japan, including 14 white and 7 colored brands. The mean difference in bergaptol, bergamottin, and 6',7'-dihydroxybergamottin concentrations in white grapefruit juice samples was 1.59, 0.902, and 1.03 times, respectively, the amounts in colored samples. White samples inhibited CYP3A-mediated testosterone-6beta oxidation in human liver microsomes by 1.04 and 0.922 times (whole juice and furanocoumarin, respectively) the inhibition by colored juice.

Thus, colored grapefruit juice may produce drug interactions at the same rate as white grapefruit juice.

https://www.ncbi.nlm.nih.gov/pubmed/18771009

But the ONLY IMPORTANT QUESTION I have is does Grapefruit have ANY concrete evidence of CYP2C19 Inhibiting Effect AT ALL?

CYP2C19 inhibition is negligible with GFJ. Things like Omeperazole have a bigger influence than GFJ on 2C19.

The mechanism of interaction is complex and connected with the influence of GJ active ingredients on prehepatic metabolism and enteric absorption pathways using p-glicoprotein (PGP) and organic anion transporting polipeptide (OATP). The main direction of GJ action is inhibition of cytochrome P450 1A2 and 3A4 isoforms

https://www.ncbi.nlm.nih.gov/pubmed/18663908

The duration of activity of grapefruit juice has been studied. In one study, consumption of a single glass (200 ml) of juice at various time intervals before felodipine showed that the extent of increase in felodipine AUC and Cmax was maximal between simultaneous and 4 h previous juice administration with drug

The half-life of effect of grapefruit juice was estimated at 12 h. Higher felodipine Cmax was still evident when grapefruit juice was consumed 24 h before felodipine. In another investigation, the effect of routine grapefruit juice consumption was evaluated [14]. One glass (250 ml) of grapefruit juice augmented mean felodipine AUC and Cmax to 267% and 345%, respectively, of that compared with water. Grapefruit juice three times daily with meals for 5 days further increased felodipine AUC and Cmax to 345% and 538% of that compared with water showing a cumulative effect of the juice.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1873672/

 

[Lorne???]

Each strain inhibits differently. Wish I could find the chart, however SOME strains/types do inhibit 2c19 significantly, and even 2D

 

[Jekyl Anhydride]

^are you referring to a strain used in juice? The varieties most widely used in commercial juices are the star Ruby/ Ruby, Marsh and Duncan. 7 other types of grapefruit or grapefruit x pomelo varieties are common but for eating and def not in a commercial juice.Flame, Lavender Gem, Melogold, Oro Blanco, Sweeties, Marsh seedless & the Thompson. Many of these are crossed back to the pomelo making them hybrids cutting the naringin & narinengen content reducing enzyme inhibition

The study I cited used 21 different juices of white and red, but the difference was truly minute.


" White samples inhibited CYP3A.. by 1.04 and 0.922 times the inhibition of colored juice. Thus, colored grapefruit juice may produce drug interactions at the same rate as white grapefruit juice."


The GFJ phenomenon seems to result from a complex synergy between naringin, naringenin, the furanocoumarins: 6',7'-dihydroxybergamottin, bergamottin, bergaptol and sesquiterpen nootkatone.. and these are just the most widely known, not counting the new and unnamed ones with only their designated UV spectra: FC 338, FC 420, FC 524, FC 530, FC 540, FC 546, FC 552, FC 570 and FC 614

Both white & red/ruby/pink contain slightly varied amounts of these so I am curious as to what "strain/ type" would inhibit 2C19 "significantly", with say the same regard as 3A4.

There's also the puumelo or pomelo along with the ama-natsu, banpeiyu, Dekopon, hassaku, hyuga-natsu, mature kinkan (Tamatama), takaoka-buntan and unshu-mikan but these had less activity then grapefruit, aside from the Carambola which was better than GF, but good luck finding that in a commercial juice.


In summation the major enzyme inhibition of (all) GFJ is CYP3A4 and to a lesser degree in order 3A5, 1A2, 2A6, 2B6, 2C9, 2C19, 2D6 & 2E1. 2C19

Although what's the benefit of 2C19 inhibition for things other than Diazepam and Tapentedol?

It's effect on Carioprodol prevents formation of Meprobamate.


Fun Fact:
Beyond it's nutrition and drug potentiation, it's shown the ability to prevent liver damage from APAP/ Paracetamol toxicity in rats.

In conclusion, GFJ and BGT prevented PARACETAMOL-induced hepatotoxicity after PARACETAMOL overdose in rats, and this calls for appropriate observation studies in humans.

https://www.ncbi.nlm.nih.gov/pubmed/28962403



https://sites.ualberta.ca/~csps/JPPS4(3)/S.Wanwimolruk/grapefruit.htm
http://jpet.aspetjournals.org/content/313/1/154
https://www.ncbi.nlm.nih.gov/pubmed/12951492
https://www.ncbi.nlm.nih.gov/pubmed/18771009

 

[Lorne???]

I meant significantly as in, a noticeable effect.Not to 3A4 degrees. It was a neat chart, alas, is lost
M

Your right though, it is a lower priority enzyme