Why does Ketamine not work well rectally?

[Jamshyd]

My experience with rectal Ketamine correlates with almost every other report I've read about it: it is not much better than taking it orally.

Does anyone know why?

If not, then I have reason to think it has to do with Ketamine's chemistry (structure, pH) preventing its absorption, rather than a metabolism issue, as it is quite effective when injected.

Once there was discussion of Gabapentin's rectal bioavailability. Someone brought up that it was a "zwitteron [sp?]" and that that somehow limits its rectal bioavailability (why?), which I frankly do not understand due to lack of chemistery knowledge. But does Ketamine posess similar qualities?

 

[negrogesic]

Im pretty certain that the rectal bioavailability of ketamine is at least somewhat higher than the oral (though i'd assume probably only 5-10% higher, and maybe half that of nasal administration and 1/4 of IM). Im not sure if this has to do with its high lipid solubity, again, unsure...

 

[Biphasic]

The low bioavailability of rectal gabapentin is due to it entering the CNS through an amino acid transporter found in the upper gastrointestinal tract rather than going through first pass metabolism and then right into plasma and through the BBB like most other drugs. The amino acid transporters are not found in the rectum.

 

[Jamshyd]

^ OH!

I was unaware of that, actually - I assumed these transporters were all over the intestines. So this means that L-Theanine would not work rectally either. That explains a lot...

But back to Ketamine... Negro, do you have specifice info on Ketamine's solubility? Then again, to my knowledge, solubility is not a big issue when it comes to rectal administration, but I could be wrong...

 

[fastandbulbous]

The amino group is 'shielded' by the aromatic ring & the cyclohexyl ring, making the polar amino group have less effect on lipid solubility - that's why PCP is so lipophillic (to the point of reabsorbtion into the bloodstream from the bladder).

Didn't know about the amino acid transporter for gabapentin though...

 

[Biphasic]

If I remember right pH has an impact on rectal absorption, and ketamine is pretty strongly acidic, but I am not sure if that has much of a bearing on anything.

Here is a neat, free PDF with comparison of intravenous, intranasal, and intrarectal ketamine administration: http://bja.oxfordjournals.org/cgi/reprint/77/2/203.pdf

As you can see, intranasal is about three and a half times as effective and the authors note that rectal ketamine is similar to oral ketamine as far as plasma levels go. The authors also note that pH may've been a factor in rectal absorption.

 

[Biphasic]

Didn't know about the amino acid transporter for gabapentin though...

Yes, it's a bit of an oddball like that, same with pregabalin but with a slightly different mechanism. Gabapentin uptake is apparently moderated by the l-type amino acid transporter and system b0,+ amino acid transport which occurs mostly in the small intestine.

 

[Jamshyd]

Thanks for all the info, biphasic and f&b.

Assuming for now that lipid solubility is not an issue... would dissolving ketamine in a basic soln. (say, water + baking soda) increase its absorption rate? Or does that not matter, since the ketamine itself remains acidic, and is left behind while the water is absorbed?

I know this question sounds byzantine, but I have very little understanding of chemistry.

Oh, and what about bassifying blood? I know (and experienced) that taking baking soda with amphetamines strongly potentiates it.

 

[negrogesic]

Aside from actual absorbtion issues, i think ketamine's potency is also greatly decreased because of the likely high level of first past metabolism. Metabolites such as norketamine(?) are probably far less active. This would in part explain the low oral and rectal bioavailabilities, and correspondingly high intranasal.

 

[Jamshyd]

^ But isn't the idea behind rectal admin, besides faster absorption, to skip first-pass metabolism?

I have reason to believe that drugs taken rectally are as invulnerable to metabolism as whent hey are taken nasally.

ps. About my previous comment on bassifying blood - I just remember that amphetamine worked extremely well rectally, so I guess that crosses that one out.

 

[B9]

I really couldn't be arsed to find out.

 

[negrogesic]

I guess I didnt put alot thought into that, sometimes i write before thinking. As you mentioned, whatever was able to to get through the mucus membrane would be put into systemic circulation. So i guess it seems almost entirely a matter of poor absorption...

I've also heard anecdotaly that menthol increase rectal absorption of stubborn compounds, although this sounds both disgusting and unpleasant. And when IM bioavailability is so high i dont see why you would need to do this (parental ketamine is the best IMO; not nearly as extreme as people make it out to be)...

 

[negrogesic]

I just looked at my copy of "Sedation and Analgesia for Diagnostic and Therapeutic Procedures" (i dont have a link but i think it is available online) and it says this about ketamine:

"Higher concentrations of norketamine are noted following oral/rectal administration because of the greater degree of first-pass hepatic metabolism and may account for a significant part of the anesthetic effect following oral/rectal administration."

This could be wrong i suppose, its probably written for physicians after all...

 

[Jamshyd]

^ I am pretty sure it is wrong, since all other sources (Jansen is the one I have right here for now) indicate to me that norketamine is actually less anaesthetic than its parent comopound and is much more psychedelic-like!!

 

[negrogesic]

I would agree, however that quotation i made is a little out of context, i think the general implication is that norketamine has ~30% the anesthetic activity of ketamine. I had no idea it was more psychedelic in nature (perhaps because of lower anesthetic properties???)...

In an article i found:

"Plasma concentrations of norketamine peaked at approximately 120 min after nasal ketamine, but appeared more rapidly after rectal administration of ketamine and were always higher than ketamine concentrations in the same situation. Calculated bioavailability was 0.50 in groups IN3 and IN9 and 0.25 in group IR9." http://bja.oxfordjournals.org/cgi/reprint/77/2/203

The IN3 and IN9 figures refer to intranasal ketamine (at different dosages), and the IR9 is the rectal ketamine. So here the rectal bioavailability is 25% to intranasal's 50%...

I am making the assumption that the norketamine plasma levels after intranasal is caused exclusively by ketamine inevitably dripping down into the stomach. Why norketamine is found in the blood relatively rapidly after rectal administration i do not know...

 

[MattPsy]

I really couldn't be arsed to find out.

:D

Ketamine is N-demethylated by CYP3A4 to norketamine. Perhaps if a CYP3A4 inducer is used a higher proportion of norketamine will be formed, thereby increasing the psychedelica and decreasing the sedation?

 

[Jamshyd]

As he would confirm, fn'b had had an experience with the opposite (K and a CYP3A4 inhibitor) and reported extreme numbness.

I have a question that is a bit out of the way but still related: Is norkeamine singular in its stereochemistry, or does it correspond to the S- and R- isomers of K?

 

[MattPsy]

It retains the chiral configuration of the ketamine enantiomer it was formed from. The potency differences remain, too (ie (S)-norketamine is more potent than (R)-norketamine).


Eur J Pharmacol. 1997 Aug 20;333(1):99-104.

In agreement with earlier studies (S)-ketamine (Ki 0.3 microM) was found to possess a 5 times higher affinity for the NMDA receptor complex than (R)-ketamine (Ki 1.4 microM). (S)-Norketamine (Ki 1.7 microM) had approximately an 8 times higher affinity than (R)-norketamine (Ki 13 microM) in the inhibition of [3H]MK-801 binding.

 

[fastandbulbous]

As he would confirm, fn'b had had an experience with the opposite (K and a CYP3A4 inhibitor) and reported extreme numbness.

I have a question that is a bit out of the way but still related: Is norkeamine singular in its stereochemistry, or does it correspond to the S- and R- isomers of K?

Suppose I should have tried a rectal dose while I was taking chlorethromycin (it's about as good an inhibitor of CYP 3A4 as you get from what I've read). Isn't it norketamine that's responsible for the gall bladder spasm side effect though? Also the culprit in ket-a-cystitis if memory serves correctly, so not the sort of thing I'd want to increase my plasma levels of

 

[Jamshyd]

I only experienced the "k-pains" once in my life, and even that may have been false alarm since I was very sick at the time. It basically felt like I was lightheaded, then stabbed in the liver, and felt as if some chemical had been released throughout my bloodstream. It wasn't so much painful as it was disturbing.

Anyways, I have reason to believe that it is actually norketamine that has the therapeutic effect I seek when I use K. It seems to me that a maintained plasma level of (small ammounts of) norketamine will produce a state of complete balance in the mind and body. The reason I suspect it is the norketamine is because the therapeutic effects last at least for a week after my last dose. So either it is norketamine lingering, or a long-term change in neuronal firing/growth patterns (possibly one leading to the other).