Benzos Estimated half life and elimination time of bromazolam & metabolites

[muaddib666]

Since there's very little data available on this topic we ( me and @BosoM ) have tried to abstract it from the closest compounds that are available in both triazolo(-OLAM) and diazepine(-EPAM) forms.
The closest one metabolically are flubromazepam and flubromazolam which are also conveniently analogues of bromazepam and bromazolam respectively.
The data for the fluoro analogues are deducted from ~10 different studies and case reports.
Elimination time = 5 half-lives of the compound, at which point 96% or less of the substance can be found in blood.

Calculation table:

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Flubromazolam - 28h half life
hydroxyflubromazolam - 38h (x 1,35 parent compound half-lives)
Elimination time (ESTIMATE): 190h (8 days)

Flubromazepam - 106h (3,78x longer then Flubromazolam)
hydroxyflubromazepam - 134,4h (x 1,26 Flubromazepam half-life)
Elimination time (ESTIMATE): 670h (28 DAYS)
Speculation to bromazepam / bromazolam, with relevant clinical data and some assumptions you can recalculate back to this:

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bromazepam - 17h
hydroxybromazepam - 20h (x 1.2 bromazepam half life)
Elimination time (estimate): 100h (4 days)

bromazolam: 3.8h (0.22x the time of the -pam compound which makes bromazepam last around 4,4 longer then bromazolam)
hydroxybromazolam: 5h (x 1.31 bromazolam half life)
Elimination time (estimate): 24-26h (1 day~)

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You can also confirm this by taking the elimination times of the fluoro analogues + metabolites (670/190)= 3.5 (flubromazepam lasts 3.5x longer then flubromazolam) and (100/26) = 3.8 (bromazepam lasts 3.8x longer in the blood then bromazolam).
This would mean that bromazolam with its main metabolite stays in your system for around 25 hours, at least.

We also considered that bromonordiazepam (desalkylgidazepam) might be a better comparison for bromazolam then bromazepam would be. Applying our calculation here, without accounting for bromonordiazepam metabolites such as the hydroxy and glucoid metabolites, because we couldn't find data for them.

bromonordiazepam: 86.7h (half-life)
Elimination time (estimate): 432,5h (18 days)

Using factor 3.78 from our flubromazepam to flubromazolam comparison.

bromazolam (86.7 / 3.78) = 22,93h
Elimination time (estimate): 114,68 (~5 days)

The lower elimination time deduced from bromazepam could be correct, as the tetrazole ring in -azolams is also susceptible to hydrolysis. But it is possible that the cyp enzyme activity increases further when switching from two to one halogen substitunent. Either way in both cases, the lactam is hydrolyzed well before the pyridine or benzene ring is attacked.

Any feedback by people with more in-depth pharmacological knowledge would be welcome!

Sources:
https://doi.org/10.1002/jms.3279
https://doi.org/10.1093/jat/bky039
https://doi.org/10.1002/wfs2.1416
https://doi.org/10.1093/jat/bkaa043
https://doi.org/10.1002/dta.2211
https://www.who.int/docs/default-so...es/43rd-ecdd/final-flubromazolam-a.pdf?sfvrsn
https://bradscholars.brad.ac.uk/bitstream/handle/10454/19320/bkad004.pdf?sequence=2&isAllowed=y

 

[snmfmy]

Researcher self-administered flubromazolam and measured pharmacokinetics lead to an estimated elimination half-life of 10 to 20 hours.

Drastically different than the commonly stated 106 hours.

Flubromazolam - Basic pharmacokinetic evaluation of a highly potent designer benzodiazepine - PubMed

Since their first appearance on the Internet in 2012, designer benzodiazepines established as an additional, quickly growing compound class among new psychoactive substances. Data regarding pharmacokinetic parameters, metabolism, and detectability for new compounds are limited or often not...

pubmed.ncbi.nlm.nih.gov

Hope that helps.

It means the earlier estimates were completely out of the ballpark or the elimination profile of flubromazolam varies wildly with CYP450 polymorphisms.

 

[muaddib666]

Researcher self-administered flubromazolam and measured pharmacokinetics lead to an estimated elimination half-life of 10 to 20 hours.

Drastically different than the commonly stated 106 hours.

Flubromazolam - Basic pharmacokinetic evaluation of a highly potent designer benzodiazepine - PubMed

Since their first appearance on the Internet in 2012, designer benzodiazepines established as an additional, quickly growing compound class among new psychoactive substances. Data regarding pharmacokinetic parameters, metabolism, and detectability for new compounds are limited or often not...

pubmed.ncbi.nlm.nih.gov

Hope that helps.

It means the earlier estimates were completely out of the ballpark or the elimination profile of flubromazolam varies wildly with CYP450 polymorphisms.

read the post again, you misread flubromazepam and flubromazolam, I added some white spaces for clarity, as both are compared in the first section of calculations

 

[snmfmy]

read the post again, you misread flubromazepam and flubromazolam, I added some white spaces for clarity, as both are compared in the first section of calculations

read the post again, you misread flubromazepam and flubromazolam, I added some white spaces for clarity, as both are compared in the first section of calculations

"More recently, a pharmacokinetic study performed in humans reported a terminal elimination half-life of flubromazepam of 10–20 h,14 whereas previous studies had reported an elimination half-life of 106 h.8,12,13."

The original article was in error. They cited the link I posted incorrectly. My apologies, I expected a peer-reviewed study to be correct with their references.

 

[muaddib666]

"More recently, a pharmacokinetic study performed in humans reported a terminal elimination half-life of flubromazepam of 10–20 h,14 whereas previous studies had reported an elimination half-life of 106 h.8,12,13."

The original article was in error. They cited the link I posted incorrectly. My apologies, I expected a peer-reviewed study to be correct with their references.

It literally says flubromazolam in your link: https://pubmed.ncbi.nlm.nih.gov/28378533/

 

[snmfmy]

It literally says flubromazolam in your link: https://pubmed.ncbi.nlm.nih.gov/28378533/

Right but the original article which i posted says flubromazepam, you can see how easily I got confused. They were wrong in the original article when they pointed to reference 14, which is the one about self-administered flubromazolam.

I didn't read the referenced article as closely as I should have because I took the original article at face value.

 

[muaddib666]

Right but the original article which i posted says flubromazepam, you can see how easily I got confused. They were wrong in the original article when they pointed to reference 14, which is the one about self-administered flubromazolam.

I didn't read the referenced article as closely as I should have because I took the original article at face value.

No worries, I've double checked the study you linked and their DOI and they indeed made a mistake citing a flubromazolam study for reference of a flubromazepam half-life. Not a surprise the authors are Chinese, is there a way to contact the author of the study or journal so they can correct the paper or retract it.

 

[muaddib666]

Right but the original article which i posted says flubromazepam, you can see how easily I got confused. They were wrong in the original article when they pointed to reference 14, which is the one about self-administered flubromazolam.

I didn't read the referenced article as closely as I should have because I took the original article at face value.

I've emailed the Ofxord Academic Journal of Toxicology Research to get this fixed, hope they do their due diligence next time.

 

[snmfmy]

I think you are making the half-life way too short, and that using the fluoro analogues of bromazepam and bromazolam ignores very clear structural relationship with elimination half-life in both classical and triazole benzodiazepines.

It also ignores the fact that bromazepam is unique with respect to all of the benzodiazepines under discussion (except pyrazolam) because it has a pyridine ring instead of the phenyl ring. Flubromazepam is structurally distinct from bromazepam because it's a fluorinated phenyl ring, not a fluorinated-Pyridine ring

Phenazepam is a 2-chloro analog that has an elimination half life of 6-12 hours.

Non-triazole benzodiazepines short half-life
Medazolam (~2hr hl) has a 2-fluoro-phenyl group
Loprazolam which has a nitro group which would make one think very long half life, has a two chlorophenyl group and it's half life is 6 to 12 hours
Even flu-nitrazepam because it has a 2-fluorophenyl group has a shorter half life than nitrazapam.
Now we look at the very short half-life triazole benzodiazepines:

Triazolam and Clonazolam (3-4hr half-life) both have a 2-Chlorophenyl group.
Using this structural assessment, It's clear that a halogen at the two position of the phenyl group is responsible for short half-life in benzodiazepines.
Bromazolam and it's triazole Structural analogs do not have a halogen at the two position on the phenyl ring

alprazolam: 12 hour el half-life (chloro versus bromo)
pyrazolam: 17 hour el half-life (pyridine instead of phenyl)
estazolam: 10-24 hour el half-life
(Alprazolam without the methyl)

I propose that it is more likely that bromazolam has a half-life of approximately 10 to 12 hours, much like its structurally similar analogs alprazolam estazolam and pyrazolam.

Respectfully

 

[muaddib666]

I think you are making the half-life way too short, and that using the fluoro analogues of bromazepam and bromazolam ignores very clear structural relationship with elimination half-life in both classical and triazole benzodiazepines.

It also ignores the fact that bromazepam is unique with respect to all of the benzodiazepines under discussion (except pyrazolam) because it has a pyridine ring instead of the phenyl ring. Flubromazepam is structurally distinct from bromazepam because it's a fluorinated phenyl ring, not a fluorinated-Pyridine ring

Phenazepam is a 2-chloro analog that has an elimination half life of 6-12 hours.

Non-triazole benzodiazepines short half-life
Medazolam (~2hr hl) has a 2-fluoro-phenyl group
Loprazolam which has a nitro group which would make one think very long half life, has a two chlorophenyl group and it's half life is 6 to 12 hours
Even flu-nitrazepam because it has a 2-fluorophenyl group has a shorter half life than nitrazapam.
Now we look at the very short half-life triazole benzodiazepines:

Triazolam and Clonazolam (3-4hr half-life) both have a 2-Chlorophenyl group.
Using this structural assessment, It's clear that a halogen at the two position of the phenyl group is responsible for short half-life in benzodiazepines.
Bromazolam and it's triazole Structural analogs do not have a halogen at the two position on the phenyl ring

alprazolam: 12 hour el half-life (chloro versus bromo)
pyrazolam: 17 hour el half-life (pyridine instead of phenyl)
estazolam: 10-24 hour el half-life
(Alprazolam without the methyl)

I propose that it is more likely that bromazolam has a half-life of approximately 10 to 12 hours, much like its structurally similar analogs alprazolam estazolam and pyrazolam.

Respectfully

It would be quite interesting to see some papers that describe the effect of the C7/R7 position substitutions of triazolodiazepines (Fl, Br, Cl, Nitro) on the half life instead of just the binding affinity / effect. It's quite unclear if the cl R7 subs have higher or lower half life then Br. It seems that the effect is stronger with the Cl sub than the Br sub, while nitro seems to be even better (in the recreational sense). But I can't find any publications on the effect of this substitution & half-life. Any sources would be much appreciated. Only thing I could possibly find is this article, but there's no way to get it without paying as far as im aware of: Theoretical structure-activity studies of benzodiazepine analogues. Requirements for receptor affinity and activity.

 

[snmfmy]

It would be quite interesting to see some papers that describe the effect of the C7/R7 position substitutions of triazolodiazepines (Fl, Br, Cl, Nitro) on the half life instead of just the binding affinity / effect. It's quite unclear if the cl R7 subs have higher or lower half life then Br. It seems that the effect is stronger with the Cl sub than the Br sub, while nitro seems to be even better (in the recreational sense). But I can't find any publications on the effect of this substitution & half-life. Any sources would be much appreciated. Only thing I could possibly find is this article, but there's no way to get it without paying as far as im aware of: Theoretical structure-activity studies of benzodiazepine analogues. Requirements for receptor affinity and activity.

I think we have to go one by one and compare.