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Pharmacology How exactly is Diazepam metabolized?

This thread contains discussion about a Pharmacology-related topic
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whiteHot

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Joined
Oct 20, 2020
Messages
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Hi all,

I want to understand more on how diazepam is metabolized and how it is eliminated in the body. On drugbank, I can see that diazepam has a lot of active metabolites like N-desmethyldiazepam, temazepam and oxazepam. Regarding the half-life, drugbank writes this:
Diazepam has a biphasic half-life with an initial rapid distribution phase followed by a prolonged terminal elimination phase of 1 or 2 days; its action is further prolonged by the even longer half-life of 2-5 days of its principal active metabolite, desmethyldiazepam (nordiazepam), the relative proportion of which increases in the body on long-term administration.
Click to expand...
That's all very informative, but what does it actually mean? I currently have these questions:
  1. How much of the initial dose of diazepam is metabolized at all? Does some remain unmetabolized and is directly eliminated?
  2. Given that many of the metabolites are active themselves, how much of the effects that we feel are actually from diazepam itself? I always had the impression that the initial high feels very different (and much better) than the later stages.
  3. After two periods of half-life have passed, how much diazepam will remain in the system? 25% of the initial dose or 0%?
  4. What exactly is the duration of action of diazepam if we include the metabolites? I only feel the comedown from diazepam after a week or so.
  5. How long does it take until you can pass a blood test after having taken a single does of 10 mg of diazepam?
I know that the answer to these questions depend on individual biology. Nevertheless, I want to understand the general principles behind them and have at least some rule of thumbs.
 
whiteHot said:
I know that the answer to these questions depend on individual biology. Nevertheless, I want to understand the general principles behind them and have at least some rule of thumbs.
Click to expand...
Those are some large questions. Only reason I found this post was because I just searched diazepam metabolites. I took 15 mgs of diazepam yesterday and wanted to know what metabolites I have rolling around me today, tomorrow, and next week. Also how long till they are all gone from the system. Was going to ask the experts on the board just out of curiosity and boredom and nerdiness. The long half life ones makes it confusing.

Got this from Google. Seems some last a long time. But I am sure on this board there are clearer answers. Maybe this is better in the N&P forum?
  • Desmethyldiazepam: The major active metabolite, found in plasma at concentrations similar to diazepam. Its terminal elimination half-life can be up to 100 hours.

  • Temazepam: A minor active metabolite that is usually not detectable.


  • Oxazepam: A minor active metabolite that is usually not detectable.


  • Nordiazepam: A metabolite that can be detected after diazepam use.


  • Temazepam glucuronide (TG): A metabolite that can be detected in postmortem blood and urine.


  • Oxazepam glucuronide (OG): A metabolite that can be detected in postmortem blood and urine.
 
JackARoe said:
Those are some large questions. Only reason I found this post was because I just searched diazepam metabolites. I took 15 mgs of diazepam yesterday and wanted to know what metabolites I have rolling around me today, tomorrow, and next week. Also how long till they are all gone from the system. Was going to ask the experts on the board just out of curiosity and boredom and nerdiness. The long half life ones makes it confusing.

Got this from Google. Seems some last a long time. But I am sure on this board there are clearer answers. Maybe this is better in the N&P forum?
  • Desmethyldiazepam: The major active metabolite, found in plasma at concentrations similar to diazepam. Its terminal elimination half-life can be up to 100 hours.

  • Temazepam: A minor active metabolite that is usually not detectable.


  • Oxazepam: A minor active metabolite that is usually not detectable.


  • Nordiazepam: A metabolite that can be detected after diazepam use.


  • Temazepam glucuronide (TG): A metabolite that can be detected in postmortem blood and urine.


  • Oxazepam glucuronide (OG): A metabolite that can be detected in postmortem blood and urine.
Click to expand...
I'm glad to see that I'm not the only one with these questions. Moving this to N&P is probably a good idea. Please move the thread.
 
Diazepam has two major metabolic pathways in humans (see Figure 1), involving either the loss of the N1-methyl group, yielding N-desmethyldiazepam, which is then oxidized at C3 to oxazepam, or the direct oxidation at C3, yielding temazepam. The elimination of oxazepam and temazepam is reviewed in sections 4.1.1 of the respective monographs in this volume. N-Desmethyldiazepam is the major circulating metabolite of diazepam, as some 50–60% of diazepam is demethylated (Bertilsson et al., 1990). The plasma concentrations of N-desmethyldiazepam approach those of diazepam following a single dose, and typically exceed those of diazepam after multiple doses, since the elimination half-life of this metabolite is much longer (50–120 h) than that of diazepam. Thus, in the data tabulated by Schmidt (1995), the half-lives of N-desmethyldiazepam are longer than those of diazepam in every situation where both were measured (in volunteers, psychiatric patients, epileptic patients, the elderly and patients with liver disease). N-Desmethyldiazepam has a longer half-life (40–120 h) than diazepam (20–54 h) in adults (Mandelli et al., 1978; Bertilsson et al., 1990)



I very much agree with something @JackARoe said once, that Benzos fucked up barbs.
Still, I had a pretty serious habit with Prince Valium for a year or two, so this thread is interesting.
The Prince is what took me to the place where I had to quit drinking, downers, etc..
 
whiteHot said:
I'm glad to see that I'm not the only one with these questions. Moving this to N&P is probably a good idea. Please move the thread.
Click to expand...
Noticed I only have the powers in PD. But let me ask if this can and should be moved.
 
Diazepam is pretty much a persistent chemical. It doesn't really get metabolized.
 
"Diazepam is N-demethylated by CYP3A4 and 2C19 to the active metabolite N-desmethyldiazepam, and is hydroxylated by CYP3A4 to the active metabolite temazepam 15,16. N-desmethyldiazepam and temazepam are both further metabolized to oxazepam 15,16. Temazepam and oxazepam are further largely eliminated by way of conjugation to glucuronic acid via glucuronidation 15,16.

Furthermore, oxidation of diazepam is mediated by cytochrome P450 isozymes; formation of desmethyl-diazepam mainly by CYP2C19 and CYP3A and 3-hydroxy-diazepam (temazepam) and oxazepam by CYP3A. Because CYP2C19 is polymorphic, extensive metabolizers (EMs), and poor metabolizers (PMs) of diazepam can be distinguished 15,16. PMs of diazepam showed significantly lower clearance (12 vs 26 mL/min) and longer elimination half-life (88 vs 41 h) of diazepam than EMs after a single oral dose 15,16. Also, PMs had lower clearance, higher AUC and longer elimination half-life of desmethyl-diazepam 15,16."

Diazepam: Uses, Interactions, Mechanism of Action | DrugBank Online

Diazepam is a long-acting benzodiazepine with rapid onset commonly used to treat panic disorders, severe anxiety, alcohol withdrawal, and seizures.
go.drugbank.com go.drugbank.com

1. Diazepam sticks around for a while, highly distributed in fatty tissue. Meta olism and clearance takes a while
2. Nordiazepam sticks around even longer than diazepam and likely changes how it feels after the metabolite builds up and diazepam stores are reduced
3. 25% left after 2 half lives, 12.5% after 3, etc...
4. Between 2 and 5 days for nordiazepam iirc
5. We can't answer drug testing questions here unfortunately
 
someguyontheinternet said:
"Diazepam is N-demethylated by CYP3A4 and 2C19 to the active metabolite N-desmethyldiazepam, and is hydroxylated by CYP3A4 to the active metabolite temazepam 15,16. N-desmethyldiazepam and temazepam are both further metabolized to oxazepam 15,16. Temazepam and oxazepam are further largely eliminated by way of conjugation to glucuronic acid via glucuronidation 15,16.

Furthermore, oxidation of diazepam is mediated by cytochrome P450 isozymes; formation of desmethyl-diazepam mainly by CYP2C19 and CYP3A and 3-hydroxy-diazepam (temazepam) and oxazepam by CYP3A. Because CYP2C19 is polymorphic, extensive metabolizers (EMs), and poor metabolizers (PMs) of diazepam can be distinguished 15,16. PMs of diazepam showed significantly lower clearance (12 vs 26 mL/min) and longer elimination half-life (88 vs 41 h) of diazepam than EMs after a single oral dose 15,16. Also, PMs had lower clearance, higher AUC and longer elimination half-life of desmethyl-diazepam 15,16."

Diazepam: Uses, Interactions, Mechanism of Action | DrugBank Online

Diazepam is a long-acting benzodiazepine with rapid onset commonly used to treat panic disorders, severe anxiety, alcohol withdrawal, and seizures.
go.drugbank.com go.drugbank.com

1. Diazepam sticks around for a while, highly distributed in fatty tissue. Meta olism and clearance takes a while
2. Nordiazepam sticks around even longer than diazepam and likely changes how it feels after the metabolite builds up and diazepam stores are reduced
3. 25% left after 2 half lives, 12.5% after 3, etc...
4. Between 2 and 5 days for nordiazepam iirc
5. We can't answer drug testing questions here unfortunately
Click to expand...
Good stuff. I remembered that it's active metabolites have active metabolites.
 
someguyontheinternet said:
"Diazepam is N-demethylated by CYP3A4 and 2C19 to the active metabolite N-desmethyldiazepam, and is hydroxylated by CYP3A4 to the active metabolite temazepam 15,16. N-desmethyldiazepam and temazepam are both further metabolized to oxazepam 15,16. Temazepam and oxazepam are further largely eliminated by way of conjugation to glucuronic acid via glucuronidation 15,16.

Furthermore, oxidation of diazepam is mediated by cytochrome P450 isozymes; formation of desmethyl-diazepam mainly by CYP2C19 and CYP3A and 3-hydroxy-diazepam (temazepam) and oxazepam by CYP3A. Because CYP2C19 is polymorphic, extensive metabolizers (EMs), and poor metabolizers (PMs) of diazepam can be distinguished 15,16. PMs of diazepam showed significantly lower clearance (12 vs 26 mL/min) and longer elimination half-life (88 vs 41 h) of diazepam than EMs after a single oral dose 15,16. Also, PMs had lower clearance, higher AUC and longer elimination half-life of desmethyl-diazepam 15,16."

Diazepam: Uses, Interactions, Mechanism of Action | DrugBank Online

Diazepam is a long-acting benzodiazepine with rapid onset commonly used to treat panic disorders, severe anxiety, alcohol withdrawal, and seizures.
go.drugbank.com go.drugbank.com

1. Diazepam sticks around for a while, highly distributed in fatty tissue. Meta olism and clearance takes a while
2. Nordiazepam sticks around even longer than diazepam and likely changes how it feels after the metabolite builds up and diazepam stores are reduced
3. 25% left after 2 half lives, 12.5% after 3, etc...
4. Between 2 and 5 days for nordiazepam iirc
5. We can't answer drug testing questions here unfortunately
Click to expand...
Thanks, that's very helpful. I'm still confused about the mechanism behind the "half-life" concept. Why is it a exponential process rather than a linear one? How can the body be more efficient at eliminating some compound at higher blood concentrations?
 
I took 15 mgs of diazepam 8 days ago. Any guess on what metabolites (if any) are rolling around in me now? I do have a fast metabolism. :) (looking over someguys info on half life of metabolites)

Have not had diazepam in years. Still being a nerd, I always disliked how long it lingers.
 
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Thanks man, I just see sometimes a 50- 200 hour half life and wonder after 5 half lives. But the 200 is probably for someone that builds it up over time. I think the math is more interesting than the drug. :)
 
The half life is only half of it
We need to figure out what concentration the drug is at in the relevant compartments and if that concentration is meaningful at the level of producing an impact on cellular and tissue function
 
Metabolism factors into half life, as does clearance. Metabolism and clearance means that drug is being removed from the blood which is then replenished from the other compartments decreasing the concentration in the tissue. Its all a connected system
 
Thanks again Someguy. I am in a stress fest at the moment (mother days from dying and father needing help). I have been taking 15 mgs twice in 2 weeks but I am thinking I can use this tool a little more without dependence worry. I think I will let myself take 15 mgs twice a week at the stressful times until things smooth out. I know I am being overly cautious. Then next week I switch to gabapentin for a night or two.

Thanks @someguyontheinternet, you know you have helped me in many ways and it is appreciated.

Also I like @DeathIndustrial88 take that benzos don't need to be too feared unless total abuse happens. If anyone sees anything wrong with short term twice a week diazepam speak up. Never even came close to a dependency and I am ok with being very cautious.

Can't wait till calmer days. But this is an interesting thread on metabolites.
 
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