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Clarithromycin, a potent inhibitor of CYP3A, greatly increases exposure to oral S-ket

specialspack

specialspack

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Eur J Pain. 2010 Jul;14(6):625-9. Epub 2009 Nov 7.
Clarithromycin, a potent inhibitor of CYP3A, greatly increases exposure to oral S-ketamine.
Hagelberg NM, Peltoniemi MA, Saari TI, Kurkinen KJ, Laine K, Neuvonen PJ, Olkkola KT.
Source

Department of Anaesthesiology, Intensive Care, Emergency Care and Pain Medicine, University of Turku, Turku, Finland. [email protected]
Abstract
BACKGROUND:

Oral ketamine is used as an adjuvant in the treatment of refractory neuropathic and cancer-related pain. Drug interactions may alter the analgesic or other effects of ketamine.
AIM AND METHODS:

The aim of the study was to investigate the effect of cytochrome P450 3A enzyme inhibition with clarithromycin on the pharmacokinetics and pharmacodynamics of oral S-ketamine in a randomized controlled cross-over study with two phases. Ten healthy subjects were pre-treated with oral clarithromycin or placebo for 4 days. On day 4, they ingested an oral dose of 0.2mg/kg of S-ketamine syrup. Plasma concentrations of ketamine and norketamine were measured for 24h. Analgesic effects were evaluated in a cold pressor test and psychomotor effects were followed for 12h.
RESULTS:

Clarithromycin increased the mean C(max) of ketamine by 3.6-fold (p<0.001) and the mean AUC(0-infinity) of ketamine by 2.6-fold (p=0.001). The relative amount of the CYP3A dependent metabolite norketamine was decreased by 54% by clarithromycin (p=0.004). Self-rated drug effect of S-ketamine was enhanced by clarithromycin (p<0.05) but other behavioral effects or cold pain scores were not affected.
CONCLUSIONS:

Clarithromycin strongly increases plasma concentrations of oral S-ketamine probably by inhibiting its CYP3A-mediated N-demethylation. This increase is reflected as modest changes in behavioral effects of oral S-ketamine.
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http://www.ncbi.nlm.nih.gov/pubmed/19897389

Would clarithromycin also have these effects on R-ketamine? As I understand it, the metabolism of ketamine to norketamine when ingested orally reduces the "psychedelic" effects and increases the sedative effects.

Could use of CYP3A inhibitors make oral ketamine a more viable ROA?
 
Contribution of CYP3A4, CYP2B6, and CYP2C9 isoforms to N-demethylation of ketamine in human liver microsomes.

Ketamine is a widely used drug for its anesthetic and analgesic properties; it is also considered as a drug of abuse, as many cases of ketamine illegal consumption were reported. Ketamine is N-demethylated by liver microsomal cytochrome P450 into norketamine. The identification of the enzymes responsible for ketamine metabolism is of great importance in clinical practice. In the present study, we investigated the metabolism of ketamine in human liver microsomes at clinically relevant concentrations. Liver to plasma concentration ratio of ketamine was taken into consideration. Pooled human liver microsomes and human lymphoblast-expressed P450 isoforms were used. N-demethylation of ketamine was correlated with nifedipine oxidase activity (CYP3A4-specific marker reaction), and it was also correlated with S-mephenytoin N-demethylase activity (CYP2B6-specific marker reaction). Orphenadrine, a specific inhibitor to CYP2B6, and ketoconazole, a specific inhibitor to CYP3A4, inhibited the N-demethylation of ketamine in human liver microsomes. In human lymphoblast-expressed P450, the activities of CYP2B6 were higher than those of CYP3A4 and CYP2C9 at three concentrations of ketamine, 0.005, 0.05, and 0.5 mM. When these results were extrapolated using the average relative content of these P450 isoforms in human liver, CYP3A4 was the major enzyme involved in ketamine N-demethylation. The present study demonstrates that CYP3A4 is the principal enzyme responsible for ketamine N-demethylation in human liver microsomes and that CYP2B6 and CYP2C9 have a minor
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The only OTC CYP2B6 inhibitor, to my knowledge, is most well known as an herbal utilized in traditional chinese medicine called Woohwangcheongsimwon. The active chemicals which causes CYP2B6 (and CYP3A4) inhibition, borneol and isoborneol, are also irritants.
 
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Bump. Came across this reference again. Has no brave guinea pig tried potentiating their ketamine with clarithromycin?
 
I think its important to consider that ketamine and NMDA antagonists in general exhibit potential neurotoxicity as well as possibly promote apoptotic lesions.

These side effects are mitigated in usual anesthetic practice in terms of ketamine so any willing guinea pig should be ready to keep that in mind.
 
specialspack said:
Bump. Came across this reference again. Has no brave guinea pig tried potentiating their ketamine with clarithromycin?
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I tried Ketamine and MXE with other CYP3A4 inhibitors and found it did work, mainly to increase the duration. I did not notice a significant change in the effects. I think that enzyme inhibitors will only work so much to affect the effects of the drugs in question.

If anyone wanted to experiment with inhibitors, I personally recommend Turmeric, black pepper and bergamot essential oil. All natural, and especially effective in combination.

h3lp said:
I think its important to consider that ketamine and NMDA antagonists in general exhibit potential neurotoxicity as well as possibly promote apoptotic lesions.

These side effects are mitigated in usual anesthetic practice in terms of ketamine so any willing guinea pig should be ready to keep that in mind.
Click to expand...

Proof. Where is the proof? How is the use of sub-anesthetic doses of Ketamine more damaging than anesthetic doses which use up to 4 times the amount required for recreational use?

Furthermore, NMDA antagonists actually exhibit neuroprotective properties, and "apoptotic lesions" aka Olney's Lesions were discredited years ago.
 
It seems hardly conclusive. Chronic ketamine users could show brain anomalies via atrophy alone (which I would relatively readily accept dissociative anaesthetics to cause), right?

Other than that Olney was quoted as reference and there seem to be a number of other half-arsed suggestions but at the core the admission that

The consequences of high doses, repeatedly administered for more than 24 h, are not known.
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So I think this:

I think its important to consider that ketamine and NMDA antagonists in general exhibit potential neurotoxicity as well as possibly promote apoptotic lesions.

These side effects are mitigated in usual anesthetic practice in terms of ketamine so any willing guinea pig should be ready to keep that in mind.
Click to expand...

was jumping to conclusions on your part.

Though I am interested to hear what you have to say on the matter. By all means I don't think dissociative drugs are to be trusted beyond a doubt and I think there are several problems associated with habitual use. For example the atrophy I mentioned. I can attest to the unhealthy nature of living a shadowy existence in the Krypts.
 
I agree with you completely on the topic of not trusting dissociative drugs on face value.

Under the header "Ketamine Neurotoxicity" the article quotes this:

"Experimentally, NMDA antagonists and ketamine are clearly
known to exhibit a potential neurotoxicity [139,140] and may
promote neuronal apoptotic lesions [141]. On the contrary, in
usual anesthetic practice, ketamine does not induce neurotoxicity.
Possible but rare neurotoxicity cases have scarcely been reported
[142]. The consequences of high doses, repeatedly administered
for more than 24 h, are not known. Psychodysleptic effects could
be linked to transient neurotoxic effects [139]. Cognitive disturbances
are frequent in ketamine chronic users [143], as well as
frontal white matter abnormalities [144]."

Thats the information my prior post was based on but on second look I can see how it may have been leaping to conclusions.

Nevertheless I still find it to be a very interesting topic.
 
Yes I know, my response was addressing the points in that paragraph.

Cognitive disturbances are obvious to associate with dissociative use since NMDA antagonism and therefore disruption of part of the cognitive system (which involves NMDA and cholinergic receptors among others) is the mechanism of action. This is not immediately fixed once the drug wears off but it is still worth investigating how reversible this effect seems to be, that time factor IMO is even more important than the fact that this happens at all. For example something like diphenidine or dizolcipine can apparently completely wipe out someone's cognitive faculties but if they are quickly restored, there are basically only acute risks to worry about. Conversely ketamine is less extreme in its effects at recreational doses, but if some part of the effects are permanent, that would really suck major ball.
As far as I can tell it is reversible for a big part, but it definitely may not be an entire reversal.

Time for longitudinal studies, right?

Sorry if the thread is being derailed - maybe someone can summarize where we stand on the original topic.
 
Interesting info but I'd never consider potentiating my ketamine with an antibiotic. No way, no how.

However, if for some reason I ever needed an antibiotic for real, then I'd be sure to request this one :P
 
Clarithromycin (like all macrolides) by itself is not without risk of fairly serious side effects. Macrolides are not the simplest of antibiotics due to their method of action. It is important from a harm reduction viewpoint to realize the CYP3A4 is, of all the CYPs involved in biotransformation, the most used. Here is a link that seems relatively comprehensive as to which ligands (substrates, substances) are associated with CYP3A4, as well as some common function modifiers (primarily inhibition/activation) in general.

http://en.wikipedia.org/wiki/CYP3A4#CYP3A4_ligands

As Foreigner said, it would be pretty ignorant to potentiate with Clarithromycin considering the broad range of less harmful CYP3A4 inhibitors out there (i.e. Naringin/Bergamottin from grapefruits). It also should be kept in mind that these substances inhibit the CYP3A4 to differing degrees, and strong modulators of the CYP enzymes (such as Clarithromycin) will almost always come with not insignificant side effects.
 
@ the very latter: would those side-effects be in any way similar to symptoms of liver diseases as a common denominator?
 
Clarithromycin and clindamycin can by the way, be absolutely brutal to the insides.

I was rx'd it recently and had to change within days to erythromycin, taking clarithromycin or clindamycin, it felt like I'd swallowed a mouthful of conc. HCl or H2SO4.
 
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