A quick question about the lipid solubility of clonazepam

[Kdem]

I found the following text (I'm not sure if I'm allowed to mention the forum):

Benzodiazepines vary in lipid solubility <abbreviated>
Benzodiazepine pKa
Bromazepam 11.0
Clonazepam 10.5 (1-position)
1.5 (4-position)
Diazepam 3.3
Flunitrazepam 1.8
Flurazepam 8.2
Lorazepam 11.5
Medazepam 6.2
Nitrazepam 10.8
Oxazepam 1.8
Prazepam 3.0

pKa is mentioned. I'm not familiar with this regarding lipid solubility. Also the '1 position' of clonazepam has a value of 10.5, and the '4' position has a value of 1.5.
So, how is the pKa relevant in this context ? And what is this about the '1' position, and the '4' position' ?

I was trying to find information about the lipophilicity of clonazepam, can someone help me make sense of these two values for this drug ?

 

[sekio]

pKa isn't lipid solubility, it's acidity/proton affinity. You want to find the 'logP' for a number that correlates to lipid solubility.

The '1' and '4' positions are the 2 nitrogen atoms in the benzodiazepine ring.

 

[Kdem]

Thanks. I had difficulty making sense of the source.

If I just look at logP, I get a bunch of numbers depending on the source.
Clonazepam, 2.7, 3.15, 2.5
Diazepam 2.82, 2.7, 2.99

That's close. I was under the impression that diazepam was much more lipophilic than clonazepam, the latter's lipophilicity being low to intermediate.
But it seems they are both equally lipophilic ? Or am I mistaken ?

 

[Zeds(NCO2CH2CH3)2]

I think you are mentally trying to match lipophilicity to its euphoric efficacy(a seemingly contradictory phrase) or maybe it's affinity.. But regardless for most compound series their sar is not basically dependent on pure lipophilicity. Consider it's metabolites and other physio chemical parameters. Nothing is simple. Hope this helps.
Zedz

 

[Kdem]

Actually, I wasn't.

I'm just trying to compare certain aspects of both drugs. Neither have ever given me euphoria.

 

[Lorne???]

I have a page somewhere which lists the lipid solubilities of 4 or 5 of the most common benzo's(including lorazepam, diazepam, clonazepam, and another one or two).

Clonazepam had the lowest solubility on the list, and was predicted to have a slow onset IV.

Of course numbers will vary from different sources, but diazepam is considerably more soluble than clonazepam, even if some sour Ed claim that clono is very similar to diazepam.

The funny thing is, various medical sources claim that clonazepam is "rapidly absorbed" and/or "rapidly crosses the BBB", but that is simply not true.

In fact if anyone has ver tried IV clono, it literally takes half an hour for the full anxiolysis effects to set in.

And I'm half awake, btw...

 

[Kdem]

Thanks for responding.

Well, the numbers I found indicated that diazepam and clonazepam had an almost similar lipophilicity.
But it's more complicated than logP, isn't it ?

I find this an incredibly difficult subject, my impression is that issues like plasma protein binding, hydophobic properties, lipophilicity, volume of distribution ... ? play a role. Clonazepam has a higher volume of distribution than diazepam (according to sources!), but one wouldn't expect that from diazepam since it 'accumulates in fatty tissues'.

I have read more than once source that states that (the unbound fraction) of clonazepam in the blood corresponds with brain clonazepam levels. I have my doubts ...

IV versus oral, that's just a different thing for many benzos.

Lorne???, would you be able to post that list, possibly with a source ? I've been trying to learn about the pharmacokinetics of the drug but I could not find much beyond what is in the PI sheets ('distributes to various tissues' really, to what extent and which ones ? is it dose releated ?)

Oh, I don't know about rapidly but I notice an effect after 20-35 minutes.

It's an old drug, are there no reliable sources that go beyond a regular PI sheet ?

 

[adder]

Where all those numbers from the post come from? Do they all relate to the acidity of protonated N1 unless stated otherwise or what? It's impossible the pKa for N1 of lorazepam and oxazepam differed so much as if we were talking about completely different classes of compounds.

 

[Kdem]

Where all those numbers from the post come from? Do they all relate to the acidity of protonated N1 unless stated otherwise or what? It's impossible the pKa for N1 of lorazepam and oxazepam differed so much as if we were talking about completely different classes of compounds.

Feel free to criticize me for the source, but it's hard to get ANYTHING.

Source: https://drugs-forum.com/forum/showwiki.php?title=Category:Benzodiazepines&redirect=no

See section 'The Chemistry of Benzodiazepines'

 

[Lorne???]

I'll try to dig it up, sir. May take a moment.

And the unbound fraction does co-relate well with clonazepam concentrations in brain, however it is a delayed effect. Remember that clonazepam is ~ 95% bound to plasma proteins, so at any given time only 5% of the drug is available to activate it's pharmacological target. The trade off is that only the same 5% is subject to metabolism by the liver, lending clono it's long half life.

Neat trick: taking to extremely protein bound drugs that are both basic(PH) will cause them to compete for proteins, and theredore increase the "free" fraction of each. It's possible to reduce protein binding to 90%, presumably doubling the amount that can cross the BBB. It will also increase clearance, however.

It's a complex drug, for sure.(but then many are)

 

[Lorne???]

Well, an old link to the paper just redirected to a useless paper about the "father of the benzodiazepines".

But an old post of me talking about it confirms it discussed nitrazepam, diazepam, lorazepam, and clonazepam, giving lipid solubilities and (hard to find) binding affinities.

I don't have exact numbers, except that clonazepam had an affinity of 0.5(ki), which was the highest on the list, and clearly extremely high. I recall diazepam had the lowest, and, IIRC, lorazepam's affinity would indicate it would be weak than 1/2 the strength of clono.

Also, clono had the lowest lipid solubility on the list, though really it was just marginally lower than lorazepam. Diazepam, the highest, by a good margin.

It was an interesting find, I'll give one more shot, as I did have it saved on a phone, but apperantly the link has been redirected.

But the info above is a good summary of what it contained, other than exact numbers, details, yada yada.

 

[Kdem]

I'd appreciate the details.

I have a question about clonazepam's lipophilicity/lipid solubility (the same?). I have seen a bunch of numbers, indicating that clonazepam's lipophilicity is not low at all. But perhaps here the matter of protein binding and hydrophobicity comes into play ?

A question or comment about your statement 'taking to extremely protein bound drugs that are both basic(PH) will cause them to compete for proteins, and theredore increase the "free" fraction of each. It's possible to reduce protein binding to 90%, presumably doubling the amount that can cross the BBB. It will also increase clearance, however'
Extremely protein bound drugs ? Diazepam is close to 100 %.
Clonazepam supposedly is at about 85 %. Anyway, how would you reduce protein binding ?

 

[Lorne???]

Most sources give clonazepam a protein binding of 90-95%; I've never seen it as low as 85%, but again, these numbers vary.

That could explain it's extended duration, though, it is odd clonazepam can last upwards of 12 hours, while even repeat doses of dzp last 4-6h.

nywy, just take to extremely protein bound drugs, both with low(similar) PH, Nd make sure they peak at the same time. If they both bind to, globulin for example, and they compete, ultimately reducing protien binding of each.

Anyway, gotta go, will try to post link to that later.

(Alas, the benzo paper is gone forever...)

 

[Lorne???]

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2976948/

That's way too long to read all the way through, but the second page rates the lipophilicity as follows:

Diazepam > Clonazepam > Lorazepam > Alprazolam

It didn't give exact numbers in the first few pages, but this basically agrees with the paper I lost.

Of course, the paper I lost claimed Clono to be even worst than lorazepam, but as I said, the number was practically identical,

I think it's quite possible that clono and lorazepam are similar, either way, but it's looking like the truth is somewhere between the center of two reported extremes.

Remember that all the benzodiazepines are hydrophobic and lipophilic in general, it could just be that some articles are stating it "low" in relative terms.

Either way their is clearly confusion surrounding the subject.

 

[Kdem]

Thanks. Confusion indeed !

Are you sure that what you stated above is not affected by the emulsion ? It's not entirely clear.
Anyway, there is no way that clonazepam is more lipophilic than lorazepam. I think I've seen numbers, but it 'hits' faster anyway (experience).
Is lipophilicity the same as lipid solubility ? Unclear.

Maybe a silly question, is it possible that clonazepam duration/availability is dependent on how much you drink (not alcohol) ? Drinking less, it lasts longer ? Just my subjective experience.

A bit of different question, now that we are talking anyway : would you happen to know (of a source) giving the (relative affinity) of various benzodiazepines to the various GABAA subunits ? Clonazepam and diazepam in particular.
I've seen the tripsit wiki (https://wiki.tripsit.me/wiki/GABA_Receptors_and_Subunits_Info), but I wonder. (those are just words, low/moderate/high) Supposedly diazepam has a high affinity for alpha 2 and 3, but somehow that doesn't seem right.
Especially diazepam's affinity for alpha 3 must be lower ? I'd actually prefer numbers, rather than words. As a point of reference, diazepam's affinity for alpha 2 and 3 compared to clonazepam.

 

[Lorne???]

Oh man, selectivity towards the various subunits, that's a whole other world of contradictions. These things are surprisingly understudied(benzo's in particular, I mean,) and especially clonazepam, to be such an old drug as you say.

They have only recently began investigating clonazepam as a possible drug for tapering other benzo's.(apperantly it has had particular success with getting patients off of alprazolam, which makes sense, given they have similar properties as highly potent benzodiazepines)

Regarding the lipid solubility, it seems lorazepam and clonazepam are basically identical in this regard. A few sources say lorazepam's is higher, but only one gave numbers.

Others say clonazepam a is higher. What is for sure is that it is lower than diazepam.

And speed of onset doesn't necessarily indicate solubility, look at methadone. For a more relevant example, you have alprazolam.

In any case, they both(clono/Ativan) have roughly the same peak, that is, 2-4h.

Clono is more variable, from 1.5-5, lorazepam 2-4, but both average 2.5-3.

I'll look around for selectivity, but, I do know clonazepam's binding affinity is around 20x higher than diazepam's.(Maybe slightly more).

Diazepam is known for being more sedating, while the nitro benzo's in general have a higher incidence of paradoxical effects.

 

[Kittycat5]

Perhaps I can help you out with the volume of distribution(Vd) issue. Vd is only a pharmacokinetic tool, it does,not in any way correlate to an actual physiological volume. It is basically a proportionality factor relating to the amount of drug in the body to the concentration measured, be it blood, plasma or some other fluid. Clinically it is most useful for calculating loading doses or figuring out how much drug was actually ingested when a plasma concentration is known. Vd of ~4 L or less usually mean the drug is confined to the plasma as it is known actual human plasma volume is roughly 4L.

Now when you look up the Vd of diazepam and clonazepam you usually find figure of 0.8-1.5 L/kg and 3.0-4.4L/kg respectively. I assume these are the numbers you refer to when you say clonazepam has a higher Vd than diazepam even though the latter is distributed into adipose tissue to a greater extent. (correct me if I am wrong). This seems counterintuitive to say the least. But you need to consider the protein binding and the units. Diazepam, being more protein bound, means more drug is sequestered in the plasma, decreasing Vd. Also, the units are in L/kg, so in a 70kg person a Vd of 4L/kg actually represents a Vd of 280 L, much higher than the 4L of plasma.

Furthermore, most drugs PK parameters follow the 2 compartment model. There is the initial rapid distribution phase (into the primary compartment, aka plasma) and the secondary slower elimination phase where it is distributed to the secondary compartment or tissue (to be specific tissue that has low blood circulation, which fat fits into). So let us take what we know about diazepam and clonazepam. Both are are quickly distributed into the blood and brain, with diazepam being slightly faster. This would be considered phase I and the Vd of either would be very similar (I have not done the math, but am quite sure this is correct). Diazepam's lipohilicity, however, also means it moves quickly out of the blood and brain and into tissue, while clonazepam does so more slowly. This would be phase II and the rapid and thorough redistribution into fatty tissue will increase the Vd. There are many ways to calculate, Vd with none being more correct than the other. It really depends on the parameters being used.

So to sum up, Vd can be variable depending on how and what we are measuring. Many studies will say things like Vd at steady state or Vd of free drug. You have to dig down into the meanings of each variable to understand exactly what the authors mean by Vd.

 

[Kdem]

Hey Kittycat5,

If we compare diazepam and clonazepam and take into account the Vd, one could still wonder where the clonazepam distributes to !
In various PI sheets one sees phrases as 'distributes in various tissues'/'concentrates in some tissues'. If I try to get more data, I read that it concentrates in bile, but not much beyond that. Muscle tissue, skeletal musle, smooth muscle, spinal cord ?
Is anything known about that ? I don't have access to paid studies.
With diazepam we know it's mostly fatty tissue. I'm not sure if clonazepam concentrates in fatty tissue to some extent.

Thanks for the explanation. I know it's hard !

 

[Kdem]

Lorne???,

My impression is that the high potency benzodiazepines have a higher relative affinity for alpha 2 and 3 compared to diazepam.
But sources are contradictory.

 

[Lorne???]

Yeah, all the high potency benzo's seem to.

Clonazepam distributed into various tissues, specifics, I'm not sure, but a large portion remains in blood, but it's mostly bound to plasma proteins, with only 10-20% available as "free" clonazepam. I've had a rough week, but over the neext few days will explore the issue further.

If you could find binding affinities(Ki values, as opposed to selectivity) that would help, as I said, that paper have clono an affinity of 0.5(Ki), by far the highest of those mentioned.(I wish I had the paper, Dzp was somewhere 10-20Ki, I think closer to the latter)

Another interesting contradiction; multiple sources claim that alprazolam is one of the most hydrophilic of the benzodiazepines(including, IIIRC, the file I recently posted, saying it was more hydrophilic than lorazepam, diazepam, and clononazepam, while also being the least lipophilic.

It makes sense it would be (relatively) hydro phillic, yet all of the published data indicates otherwise, with most sources giving alprazolam a solubility of 0.04mg per ml, vs clono, which is usually listed at 0.09mg(90mcg)/ml, though others are more vague, simply listing it(clono solubility) as <0.1mg/ml.
Either way, implies quite strongly the opposite. But these values are usually at PH 7, perhaps at lower ph(like in the GI) alprazolam's solubility dramatically increases?

But yeah, it's odd. I can attest that clono solubility in water is at least close to the 90mcg/ml value, with xannie, I've no clue.

I'd like to dig up another binding affinity chart, but they can be hard to find(without paying money, that is)

Nice to have someone to bounce these questions/ideas with.

(Oh, and clonazepam is actually approved as a (skeletal?) muscle relaxer, and is also used off label as a co-analgesic, i dont know if that affects anything, but hey...)

(Hopefully) a final word: Kitty brings up good points, but these numbers in this case still aren't adding up. But clono clearly penetrates the BBB more slowly, which naturally leads to a longer duration, but it wouldn't explain it's 8-12+ hour duration, vs Dzp's 3-6(max 8, sometimes just 1.5-2) duration, but there are simply too many variables in play)