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Pharmacokinetics of clonazepam/Rivotril, German source, questions

K

Kdem

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Mar 14, 2015
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Since I'm able to read German up to a point, I did read the German wiki for clonazepam.

The information was a bit different from what I'd gotten earlier.

https://de.wikipedia.org/wiki/Clonazepam Ein kleiner Teil wird chemisch umgebaut und dann erst ausgeschieden. Die Plasmahalbwertszeit beträgt etwa 30–40 Stunden.[3] Der Anteil, der an die Eiweißmoleküle im Blut gebunden ist (Plasmaproteinbindung), liegt bei 83–87 %, die Bioverfügbarkeit bei 71–76 %. Es wirkt über die verstärkte Hemmung GABAerger Nervenzellen und bindet am GABAA-Rezeptor.
A bioavailability of 71-76 %, not the same as medsafe.govt.nz/profs/Datasheet/r/Rivotriltabdropinj.pd

Checking wiki's definition of bioavailability, 'In pharmacology, bioavailability (BA) is a subcategory of absorption and is the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered intravenously, its bioavailability is 100%.[1] However, when a medication is administered via other routes (such as orally), its bioavailability generallyTH[›] decreases (due to incomplete absorption and first-pass metabolism) or may vary from patient to patient. Bioavailability is one of the essential tools in pharmacokinetics, as bioavailability must be considered when calculating dosages for non-intravenous routes of administration.'

So if I understand correctly, a very large part does not reach the CNS. Why would this be so ? Especially, since diazepam's bioavailability is 100 % (oral).

Is anyone able to get me the German PI sheet for Rivotril ? Apparently, it's not for public use ...

Sorry about the messy format, I can't get it fixed.
 
Because of what do you think that a very large part of it does not reach CNS?

Bioavailability of 71-76% is an average value for an oral pharmaceutical, but this only tells how much gets in the bloodstream (means a loss of 29 - 24% of the dose compared to i.v.). The CNS permeability is another thing that is not mentioned here.
 
Kdem said:


So if I understand correctly, a very large part does not reach the CNS.
Click to expand...

No, "the systemic circulation". From there it goes to whole body. How much in the CSN, it a a pretty complex question.
 
Not to be argumentative, but if it doesn't reach systemic circulation it will not reach the CNS ? At least, for the most part ?

As for diazepam, I was mislead by wikipedia which claims an oral bioavailability of 100 %. Various sources, various numbers. https://www.ncbi.nlm.nih.gov/pubmed/6849499 'Absolute bioavailability averaged 94%, indicating essentially complete absorption.'
https://one.nhtsa.gov/people/injury/research/job185drugs/diazepam.htm 'Oral bioavailability is approximately 100%'.
In any way, the drug is extremely lipophilic so under normal circumstances I would expect a near 100 % absorption. (one could even question if all tablets in the studies mentioned contained the indicated amount of diazepam).

I'd still appreciate any answer to my questions.
 
Well, about clonazepam specifically: https://books.google.nl/books?id=6X...nepage&q=clonazepam first pass effect&f=false 'although clonazepam is extensively metabolized, its long t0.5 excludes the possibility of a first pass effect after p.o. doses.'

And http://www.pharmacology2000.com/General/Pharmacokinetics/kinobj1F.htm '


  • Major factors that reduce bioavailability to less than 100%:
    ​
    • Incomplete absorption
      ​
    • First-pass effect (liver metabolizes drug before drug reaches systemic circulation)' (oops!)


      ​
 
Kdem said:
Not to be argumentative, but if it doesn't reach systemic circulation it will not reach the CNS ? At least, for the most part ?

As for diazepam, I was mislead by wikipedia which claims an oral bioavailability of 100 %. Various sources, various numbers. https://www.ncbi.nlm.nih.gov/pubmed/6849499 'Absolute bioavailability averaged 94%, indicating essentially complete absorption.'
https://one.nhtsa.gov/people/injury/research/job185drugs/diazepam.htm 'Oral bioavailability is approximately 100%'.
In any way, the drug is extremely lipophilic so under normal circumstances I would expect a near 100 % absorption. (one could even question if all tablets in the studies mentioned contained the indicated amount of diazepam).

I'd still appreciate any answer to my questions.
Click to expand...

They are both pretty lipophilic.

Diazepam LogP: 2.82 (https://www.drugbank.ca/drugs/DB00829)
Clonazepam LogP: 2.41 (https://www.drugbank.ca/drugs/DB01068)

AFAIK a LogP of 2 is considered optimal for a drug.
 
Someone once told me 'pharmacokinetics is complicated'. In my experience, clonazepam is far less lipophilic than lorazepam or diazepam. I guess LogP doesn't mean everything.
 
Kdem said:
Someone once told me 'pharmacokinetics is complicated'. In my experience, clonazepam is far less lipophilic than lorazepam or diazepam. I guess LogP doesn't mean everything.
Click to expand...

So you are dismissing objective and scientific logP experiments because of your subjective experience?

LogP actually does mean everything when it comes to measuring lopophilicity. It certainly means more than a subjective guesstimate based on "experience".
 
I'm not dismissing logP, it's that there are many variables. As I said 'pharmacokinetics is hard'. For example, diazepam is very lipophilic and is distributed quickly to the brain and other target sites. Much faster than clonazepam. It's not just my personal experience. Please don 't ask me to explain ! I guess I could quote something, but it's not as if I understand these matters so well.
 
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