Sublingual & Nasal Administration By Pass The Liver?

[muie]

Nasal & sublingual administration, like injections are said to by-pass the liver and thus avoid first-pass metabolism! As far as I know first-pass metabolism is responsible for almost all active metabolites. Avoiding the liver, in turn avoids liver damage!

This doesn't sound right however

My understanding has been that no matter the ROA, once the drug enters the blood *everything* passes through the liver! Even intravenous, while not being subject to first-pass metabolism, it still has to pass through the liver once its in the blood.

Lets take something popular, oxycodone for example, when taken orally & going via 1st pass metabolism the main metabolite is oxymorphone, while 75% oxycodone remains un-changed. This would mean that if one were to take the same dose of oxycodone via a different MOA such as nasal or sublingual, avoiding first-pass metabolism, in turn produces effects devoid of oxymorphone, only with those of oxycodone!

If this is true however, then why even when snorting oxycodone, does the methadone urine test detect a positive for oxymorphone? BTW in case you didn't know, the methadone clinics always test the urine for the metabolite of the parent drug, for example in the case of methadone the metabolite is EDDP. The metabolite for the parent drug fentanyl is norfentanyl, and so on with other examples.

If acetaminophen were administered sublingually, would it still produce the toxic metabolite that first-pass metabolism creates?
Would this mean that if acetaminophen and acetaminophen opioid pain medications could be either taken sublingually or nasally, that nobody would ever worry of liver damage again?

Am I wrong? Are active metabolites created regardless of MOA?

I hope that someone can shed some light and illuminate this topic once and for all!

1. Do sublingual & nasal avoid the liver?
2. What implications does this have on metabolites of the particular chemical (are they still produced?!)?
3. Finally, would liver damage still be an issue if MOA used is either sublingual or nasal?

ps. Between sublingual and nasal I've definatley got more experience with nasal though never via nasal sprays so a more accurate description of my experience is rather best described as snorting/insufflation!

 

[Solipsis]

AFAIK:

Nasal and sublingual administration avoid first-pass effect where you have metabolism before most of the drug can reach the brain... that way you need less of the drug for effect and in net value this may limit toxicity as levels are lower.

But you are generally right that any bit of the drug that does not enter the brain or leaves the brain still all ends up in systemic circulation. From there it still goes to the liver and from there via the heart to the kidneys.

It depends on the drug whether it can be excreted well through the kidneys unmetabolized or not. Plenty of drugs need to first be metabolized to become proper candidates for renal excretion.

If you take ketamine for example: oral dosages are rather high because via first-pass metabolism a lot of it turns to norketamine so you are left with less ketamine. With other drugs the bioavailability may not be so varied, and you inevitably get roughly the same sort of effect from a dose.
I guess there may be differences in ratios of drug and metabolites over time depending on the ROA (MOA is mechanism of action, ROA is route of administration), so with some drugs you may be stretching metabolism and it may perhaps be less taxing. But it all depends on so many factors, because on the other hand exposure can be longer if metabolism gets backed up.

All in all, I think such ROAs hardly if ever lead to less direct toxicity, but lower needed doses can indirectly help and the kinetics may play a beneficial role: possibly you can avoid getting a sudden high concentration of primary metabolite (say it's toxic), when you first distribute the drug over your body's tissues.

In the case of paracetamol, it depends on what big an amount is metabolized by a specific CYP450 subtype to produce the toxic metabolite. I can't think of a way the ROA influences that.

 

[sekio]

Oral administration just means that the drug is subject to metabolism by the liver before it reaches the bloodstream, as well as during. All drugs in the blood will eventually pass through the liver regardless of their route of administration, though, so all that switching from oral to an alternate ROA really does is increase the amount of unchanged drug that is absorbed and decrease the amount of metabolites formed inititally.

This means acetaminophen is still toxic when taken e.g. IV or rectally. There is no way to administer a drug in vivo and have it not be subject to metabolism/excretion, FYI.

 

[aced126]

From the gastrointestinal tract, there is a blood vessel called the hepatic portal vein which directly leads to the liver, where hepatocytes can start to metabolise exogenous chemicals.

 

[DotChem]

AFAIK:

If you take ketamine for example: oral dosages are rather high because via first-pass metabolism a lot of it turns to norketamine so you are left with less ketamine...

Which makes me wonder if all the hopplas about IV ketamine fast antidepressant activity is not just due to placebo. Since the first pass metabolite of ketamine (Hydroxynorketamine) is shown to be responsible for its AD activity, then logically oral rather than IV ketamine should show AD activity. Or at least, ORAL ketamine should be superior to the commonly used infusion of Ketamine since it will be converted via first pass metabolism to the active metabolite HNK. Unless the response to IV ketamine is just placebo! (but then again even rats respond!?)..wait! is there a placebo effect in rats?
OP: interesting question: I always thought "bypassing first pass metabolism" by changing ROA is used a bit too liberally. More like "pospo first pass metabolism" rather than bypassing it

 

[serotonin2A]

Which makes me wonder if all the hopplas about IV ketamine fast antidepressant activity is not just due to placebo. Since the first pass metabolite of ketamine (Hydroxynorketamine) is shown to be responsible for its AD activity, then logically oral rather than IV ketamine should show AD activity. Or at least, ORAL ketamine should be superior to the commonly used infusion of Ketamine since it will be converted via first pass metabolism to the active metabolite HNK.

HNK may be gluconurated during first-pass metabolism, which would inactivate it. HNK may only be a minor metabolite after p.o. ingestion.

OP: interesting question: I always thought "bypassing first pass metabolism" by changing ROA is used a bit too liberally. More like "pospo first pass metabolism" rather than bypassing it

"First-pass" refers to metabolizing something BEFORE it enters systemic circulation. What you are describing isn't postponed first-pass metabolism, but rather is just simply biotransformation.

 

[Cotcha Yankinov]

Do you think that glucorodination inhibitors would be an effective or even practical way to increase HNK levels?

 

[aced126]

Do you think that glucorodination inhibitors would be an effective or even practical way to increase HNK levels?

Maybe, but given the diverse and non-specific role glucuronidation metabolism plays in the body (e.g metabolism of various steroid compounds), this probably wouldn't be a practical way to increase HNK concentration.

 

[serotonin2A]

Do you think that glucorodination inhibitors would be an effective or even practical way to increase HNK levels?

I wasn't trying to suggest that gluconuration is the only reason that ketamine isn't very active p.o. But if it is, then theoretically inhibiting phase II biotransformation might help. But as aced126 noted, that isn't a practical approach.

 

[DotChem]

HNK may be gluconurated during first-pass metabolism, which would inactivate it. HNK may only be a minor metabolite after p.o. ingestion.

That's exactly my point: IV ketamine will result in even LESS phase I metabolite as the drug will be eliminated (renal) before it has chance to undergo hydroxylation. As opposed to p.o ROA where it would undergo liver first pass and get converted to HNK. You end up with even lower levels of HNK by IV-ing. So theoretically at least, p.o. ketamine should be more (not less antidepressant) than IV'ed.

HNK may or may not be gluconurated: because it is so polar, there is no need for the body to do that. It will propoably be excreted via renal along with polar stuff. driving force: thermodynamic control just like ethanol EtOH is eliminated as such without getting conjugated!

"First-pass" refers to metabolizing something BEFORE it enters systemic circulation. What you are describing isn't postponed first-pass metabolism, but rather is just simply biotransformation.

I dont get it.. first pass: stomach > mesenteric portal vein > liver > metabolite > general circulation
second phase: general circulation > gluconoridation (or other conjugation like acetylation) of unmasqued reactive functional group formed during first pass)
then elimination

So if you by pass first-pass (eg IV ROA) your drug have more chance of getting eliminated before undergoing any "biotransformation" assuming it is not excessively lipophilic. So you'll be pissing the drug unchanged. Question really is: to what extent liver metabolizing enzymes (Phase I enzymes) have the chance to react with the drug before it geting eliminated?? The example of Ketamine AD activity is interesting one because the first pass metabolite HNK is the active specie and the drug beeing offered as IV. having needle stuck and being infused for hours is a sure way to elicit a placebo effect especially for conditions like Depression where it is so strong...That was the question I was pondering..

 

[Black]

I dont get it.. first pass: stomach > mesenteric portal vein > liver > metabolite > general circulation
second phase: general circulation > gluconoridation (or other conjugation like acetylation) of unmasqued reactive functional group formed during first pass)
then elimination

first pass simply means that it passes by the liver first before it reaches general circulation.
any further passage by the liver will of course be identical. if a drug is heavily metabolised by the liver (oxidised by some cyp450 or whatever), there will be a lot metabolised every time it passes by the liver. if a drug is mainly eliminated renally, first pass metabolism by the liver will not make a lot of difference.

edit2:
you are confusing first pass with phase I. these things are completely independant. first pass means passage by the liver before it gets into the blood stream. phase I means the drug is oxidised (or hydrolysed or whatever) to differntiate that step from phase II where the phase I product is conjugated with some sugar. you can have phase I and phase II during first pass metabolism. and phase I can still happen after first pass metabolism.

edit:
wiki's ketamine entry says:

Oral ketamine is easily broken down by bile acids, thus has a low bioavailability (about 20%).

so if this is true, the ketamine broken down by bile acids won't produce the same degradation products you'd get from hetapic metabolism. therefore most of the ketamine you give orally is lost, making the whole rout of administration pretty ineffective.

 

[serotonin2A]

That's exactly my point: IV ketamine will result in even LESS phase I metabolite as the drug will be eliminated (renal) before it has chance to undergo hydroxylation. As opposed to p.o ROA where it would undergo liver first pass and get converted to HNK. You end up with even lower levels of HNK by IV-ing. So theoretically at least, p.o. ketamine should be more (not less antidepressant) than IV'ed.

NO. Ketamine itself has no hydroxyl group and thus cannot be glucuronidated without first being hydroxylated to HNK. It could be converted to HNK > HNK glucuronide > kidney during the first pass. That could eliminate a lot of ketamine. By contrast, with IV, conversion to HNK would be slower, so glucuronidation would also be slower.

HNK may or may not be gluconurated: because it is so polar, there is no need for the body to do that. It will propoably be excreted via renal along with polar stuff. driving force: thermodynamic control just like ethanol EtOH is eliminated as such without getting conjugated!

No need to speculate about this because the answer is known...

"Two glucuronide conjugates of hydroxynorketamine were also identified."
http://www.ncbi.nlm.nih.gov/pubmed/19448136

"The remaining 80% was probably excreted conjugated with glucuronic acid."
http://www.ncbi.nlm.nih.gov/pubmed/1155748

I dont get it.. first pass: stomach > mesenteric portal vein > liver > metabolite > general circulation
second phase: general circulation > gluconoridation (or other conjugation like acetylation) of unmasqued reactive functional group formed during first pass)
then elimination

So if you by pass first-pass (eg IV ROA) your drug have more chance of getting eliminated before undergoing any "biotransformation" assuming it is not excessively lipophilic. So you'll be pissing the drug unchanged. Question really is: to what extent liver metabolizing enzymes (Phase I enzymes) have the chance to react with the drug before it geting eliminated?? The example of Ketamine AD activity is interesting one because the first pass metabolite HNK is the active specie and the drug beeing offered as IV. having needle stuck and being infused for hours is a sure way to elicit a placebo effect especially for conditions like Depression where it is so strong...That was the question I was pondering..

You are missing the point. The name for the phenomenon we are talking about is "first pass metabolism" not "first pass elimination". The reason that the first pass effect reduces bioavailability is that enzymes in the gut and liver (CYP, MAO, UDP, carboxypeptidases, etc) have a chance to metabolize the drug before it enters systemic circulation. So for CNS active drugs, there can be a massive reduction in drug concentration as it travels from gut > liver > circulation > brain. By contrast, after IV, the drug enters systemic circulation immediately and then is slowly exposed to the liver.