clonazepam metabolism

[burntorangebl00d]

To quote wikipedia's article on Clonazepam, 'Clonazepam does not produce any pharmacologically active metabolites. The metabolites of clonazepam include 7-aminoclonazepam, 7-acetaminoclonazepam and 3-hydroxy clonazepam.'

Do these metabolize into anything else?

For example, I know that diazepam metabolizes into 'nordiazepam, temazepam, and oxazepam.'

Thanks yall.

 

[seep]

Be skeptical of anything you read on Wikipedia regarding any benzodiazepine. There's currently an editing war going on in those articles; some very biased research is being cited as the consensus of the medical and scientific communities. One person in particular is methodically trying to hijack every benzodiazepine article.

 

[Hammilton]

what a bastard!

I'd be surprised if 3-hydroxy-clonazepam was entirely without activity.

 

[burntorangebl00d]

You know I was wondering about that, with Wikipedia having some information that was less than accurate... I was under the impression that most benzodiazepines metabolize in one way or another into oxazepam, or nordiazepam. And it suprised me that clonazepam didn't have any active metabolites. Hmmmm.

I wonder why that particular individual is trying to hijack the benzo wiki info? That's a very strange bird.

 

[Hammilton]

Obviously oxazepam or any diazepam derivative won't result. Where clonazepam has a nitro group where the diazepam derivatives have chlorine atoms. None of the nitro benzos will have 7-chloro metabolites. At least, I'd be awfully surprised to find any.

 

[burntorangebl00d]

Klonopin's manufacturer Roche had this to say: 'The half-life of the parent compound varied from approximately 18 to 50 hours, and the major route of excretion was in the urine. In humans, five metabolites have been identified. In general, the biotransformation of clonazepam followed two pathways: oxidative hydroxylation at the C-3 position and reduction of the 7-nitro function to form 7-amino and/or 7-acetyl-amino derivatives.'

So that's two addtional metabolites omitted in the Wikipedia article...

Then Medsafe had this to say: 'Clonazepam is extensively metabolised by reduction to 7-amino-clonazepam and by N-acetylation to 7-acetamino-clonazepam. Hydroxylation at the C-3 position also occurs. Hepatic cytochrome P-450 3A4 is implicated in the nitroreduction of clonazepam to pharmacologically inactive metabolites. The metabolites are present in urine both as free and conjugated (glucuronide and sulphate) compounds.'

Medsafe also listed the mean half-life as 30 to 40 hours, not the 20 to 80 listed on Wikipedia.

 

[Black]

look here on page 17.

 

[burntorangebl00d]

Thanks Black... I read on page 17, but I'm still a little confused as it said that 'the intermediate nordiazepam and oxazepam metabolites are active as BZ-receptor ligands.' So, that means that clonazepam does in fact, at least at some point, metabolize into nordiazepam and oxazepam?

 

[seep]

Thanks Black... I read on page 17, but I'm still a little confused as it said that 'the intermediate nordiazepam and oxazepam metabolites are active as BZ-receptor ligands.' So, that means that clonazepam does in fact, at least at some point, metabolize into nordiazepam and oxazepam?

Clonazepam is "the intermediate nordiazepam metabolite" because it is N-1 unsubstituted (i.e. -NH at N-1). The key mechanism of action in clonazepam involves the reduction of its 7-nitro group, after which the magnitude of psychoactivity of the "less active" 7-amino metabolite becomes the question. In other words, how much GABA-a affinity does 7-amino clonazepam possess?

It seems, though, that the statement you originally had qualms with, that "clonazepam does not produce any pharmacologically active metabolites," is probably misleading (and notice the references cited in that section of the wiki article are from 1987, 1978 and 1977).

 

[Hammilton]

Given that without a halogen or pseudohalogen activity is either absent or nearly so, whatever activity 7-amino-clonazepam has will be irrelevant, as the EC50 will never be reached, so there will be no activity.

If there's any active dose for 7-amino-clonazepam, you're pretty sure to be looking in the 100's to 1000's of mg's.

edit: 30 seconds of searching says I'm right:

Residual effect of a 7-amino metabolite of clonazepam on GABAA receptor function in the nucleus reticularis thalami of the rat
Mitsutoshi Munakata and Shigeru Tsuchiya
Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan
Address correspondence to Mitsutoshi Munakata, M.D., Ph.D., Department of Pediatrics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan. E-mail: [email protected]
Copyright Copyright © 2008 by the International League Against Epilepsy
KEYWORDS
7-aminoclonazepam • Clonazepam • GABAA receptor • Benzodiazepine re-ceptor • Nucleus reticularis thalami • Withdrawal symptoms
ABSTRACT

A considerable amount of 7-aminoclonazepam (ACZP), a major metabolite of clonazepam (CZP), is present in the brain during CZP treatment, yet the pharmacological properties of ACZP remain unknown. We investigated the effects of ACZP on the GABAA receptor-mediated currents (IGABA) in neurons from the nucleus reticularis thalami (NRT) of the rat, using a nystatin-perforated patch technique. Neurons in which CZP (10 nM) exerted prominent augmentation (>100% augmentation) of IGABA, which comprised 32% of the neurons tested, were included for the analysis of ACZP. In these neurons, ACZP augmented IGABA, which was blocked by 10 μM flumazenil, a benzodiazepine receptor (BZR) antagonist. The half-maximal effective concentration of ACZP was 124 nM, whereas that of CZP was 1.8 nM. The maximal enhancements induced by ACZP and CZP were 38% and 170%, respectively. In neurons from the ventrobasal complex of the thalamus, the effect of ACZP was negligible. Our results suggest that ACZP was a weak partial BZR agonist and that ACZP may competitively modify the effect of CZP, leading to clinical consequences for patients with high levels of ACZP.


http://www3.interscience.wiley.com/journal/120120311/abstract?CRETRY=1&SRETRY=0

 

[Hammilton]

Interestingly, though the document doesn't actually say so, it gives just about everything you would need to know to come up with recreational benzodiazepine prodrugs. Avizafone doesn't qualify imho. I haven't tried Rilmazafone, though; it looks like it might be recreational.