C Y P D Crazy!! Inhibitor/Inducer Confusion

[PillFreak]

HI All....

I am still HORRIBLY confused about inducers & inhibitors. I have already read the posts on CYPD's but they are from 2008+, very lengthy & very confusing to me. I had my 'Pharmaceutical DNA test done, so I know the specific 'enzymes' to my body.

Anyway, I have been taking hydrocodone meds for 10yrs. Approx 3 months ago, they seem to abruptly stop working. I told my PM doc,and he assumed they had just run their course, due to amount of time I was on & off of them. My DNA profile came back as a 'normal'metabolizer for Tramadol, codiene, hydrocodone & oxycodone. I apparently don't metabolize any others i.e.- Fentynal, oxymorphone, Hydromorphone etc. (He attempted to put me on the last 3 meds..DUH!!). Needless to say they did not work.. Out of frustration I read threads here as to how to attempt to potentiate these meds for SOME relief. The only help was 'plugging' the Hydromorphone. Not to mention, the almost TOO HIGH buzz feeling Whoa!

After dissecting my DNA profile, I realized that venlafaxine HCI ER was a CYP2D6 inhibitor, I also realized I had started taking this approx 3 months earlier. About the same time my hydrocodone STOPPED WORKING.

I guess my real questions are... Has anyone else experienced extremely diminished effects of hydrocodone after taking similar CYP2D6 inhibiting drugs? And what can I do to be able to take both meds, so that I don't have to jump to these 'big boy' drugs before their time? Why are some many threads saying to take, eat or drink things to inhibit the CYP2D6, when it seems to diminish the effect of these opiates? (Specifically hydrocodone for me) Is there ONE formula, SPECIFIC for only hydrocodone, when it comes to inducing and/or inhibiting specific enzymes? I would love to know how & why these inhibitors/inducers actually work/impede receptors, if anyone has knowledge. I have already read what drug is metabolized from one drug into another, and at this point, it's extraneous information. I don't care about the names that anything turns into, I only care about making it work like it use to. On a similar note, has anyone tried the new hydrocodone XR? Zohydro I believe is what it's called. It literally just hit the market a few weeks ago. (USA) Would love to hear any feedback on that!! That seems like it would be a God send for my condition.

I am a 45yo female who is as healthy as a 30yo, except for my 70+ yr old back. I'm not a candidate for surgery at this point, so I need to try and keep my tolerance as low as possible, in an to attempt to outlive the available meds on the market. And to be honest, it would be nice to have a few "recreational" days if that's even still possible %)

Thank you all so much, in advance!! I think this a great site and I'm thrilled that I stumbled onto it!! I hope I did not ramble too much!!! I'm hitting the ADHD threads after posting

Miché

ps-- I see my PM doc on Thurs. I'm going to ask for zohydro. If successful, I'll be sure to give a complete and accurate report of ALL effects... Wish me luck!!

 

[Kittycat5]

Enzyme inducers/inhibitors do not affect the receptors where drugs work, they make the liver be able to either break drugs down more or less effectively. Inducers usually cause an over expression of the enzyme responsible for metabolism, thus leading to more breakdown of the drug. Inhibitors bind tightly to the enzyme not allowing it to be free to do its job of metabolism.

Drugs can have multiple pathways of metabolism. Hydrocodone is metabolized by both 2d6 and 3a4, for instance. Interfering with either pathway can effect blood concentration of the drug. Venlafaxine is not a particularly strong inducer, however of 2d6 so not sure if taking this had any effect on your hydrocodone.

 

[PillFreak]

Thanks for the reply. It did she'd some new information for me, just not 100% of what I'm looking for. Thank for the information you did give

 

[Kittycat5]

No prob. What else did you want to know?

 

[PillFreak]

Any specific combo of inducers/inhibitors to be able to take my antidepressant as well as hydrocodone and still get pain relief without over taking norcos. My PM doc is about to drop me because of it.

 

[PillFreak]

I know this is 'off thread' do you have any experience with plugging oxycodone? I have 3 left. Last time in mixed with warm-hot water, it stayed very granularly at the bottom of bottle. I plugged anyway. Once I used the restroom again, the same pink gran duals came out in clumps as if they never dissolved. They are the only 3 pain meds I have left until my pharmacy gets my zohydro in tomorrow morning! And I need to get the most of them... Oh their 10s

 

[Kittycat5]

Ive never plugged oxy. Just sniffed or swallowed. It has a pretty high oral bioavailabilty so plugging usually is not much more effective. I am thinking about your other problem but stumped. As I said venlafaxine has negligable effects on CYP450 enzymes. Do you take other meds or could tolerance be the issue?

 

[PillFreak]

I only know the venlafaxine ER is a CYP2d6 inhibitor. I was not getting to same relief I had in the beginning of course, but it (Norco) was still doing the job ok... When I say it stopped, I mean IT STOPPED! In it's tracks! The absolute only change was the venlafaxine! I've read other threads here were some were experiencing the same issues, and ev1 told them it couldn't be the anti-D's, but I KNOW at this point that's what it is... No tapering of tolerance, nothing else added or subtracted etc..

 

[Kittycat5]

I dont have an answer. Hydrocodone goes to hydromorphone via CYP2d6 which is a bit stronger. But studies show inhibiting the enzyme does little to affect the effects of hydrocodone. I hope the zohydro works out for you. Pain sucks.

 

[PillFreak]

Yes pain sucks out loud!! Thanks for all of your input. It is appreciated! I spoke with a pharmacist friend, he has a great theory. Drug to drug interaction. Venlafaxine ER is a stronger molecular drug. The opiates may bind to those and basically may become bullied, taken over and/or absorb the weaker med. What is then left in the system after that, could be effected by rapidly clearing depending on if your a ultra rapid, immediate etc. metabolizer... Food for thought!

 

[Bob Loblaw]

~~~> od

 

[PillFreak]

Bob, what does ~~~>od mean??

 

[Kittycat5]

It just means he moved it from homeless threads to other drugs. What do you mean by one is a stronger molecular drug?

 

[crOOk]

I know this is 'off thread' do you have any experience with plugging oxycodone? I have 3 left. Last time in mixed with warm-hot water, it stayed very granularly at the bottom of bottle. I plugged anyway. Once I used the restroom again, the same pink gran duals came out in clumps as if they never dissolved. They are the only 3 pain meds I have left until my pharmacy gets my zohydro in tomorrow morning! And I need to get the most of them... Oh their 10s

If you want to plug the oxy you need to grind down on it with a lot of force. Ime the bottom of a spoon works for this, but the little pellets will jump all over the place. you can put them in a very large cooking pot or wrap them in paper while you grind them. Once the paper has holes you switch to a new one until youve got powder and torn pellet coating left. This you can dissolve in water (not the membranes, but those are inactive anyway) and squirt up your rectum.

[Removed information about the pharmacokinetics of rectal vs. oral oxycodone, since it was false. See Lorne???'s post above for more accurate information]

Yes pain sucks out loud!! Thanks for all of your input. It is appreciated! I spoke with a pharmacist friend, he has a great theory. Drug to drug interaction. Venlafaxine ER is a stronger molecular drug. The opiates may bind to those and basically may become bullied, taken over and/or absorb the weaker med. What is then left in the system after that, could be effected by rapidly clearing depending on if your a ultra rapid, immediate etc. metabolizer... Food for thought!

He could be trying to say they are competing for CYP2D6 (they are both metabolized by that), so your hydrocodone ends up being metabolyzed by the other cytochrome P450, namely CYP3A4. The thing is that this is pretty much just competitive inhibition and from what I could gather venlafaxine is supposed to be a weak inhibitor of CYP2D6.

This sounds more probable than having no explanation, but still isn't very obvious and would be slightly unusual. The other possibility would be venlafaxine having some sort of effect on how you are processing pain.

Either way I would say it sounds like the venlafaxine is doing something here that it shouldn't, causing you to experience more pain. I would talk to your doctor about switching to another antidepressant, venlafaxine is special in many ways. Surely you will find one that is better suited. Make sure it isn't inhibiting CYP2D6 and you might be fine with your old pain med dosage, it seems preferable to me to mess with your only recently introduced antidepressant over messing with your pain medication that has been working fine for a decade.

 

[Lorne???]

I'm sorry, but what your saying about rectal oxycodone makes no sense. First off, tmax with rectal dosing is (typically) longer than oral, so peak effects are delayed. And the BA is roughly the same(40-90% on both counts, though rectal might be less erratic, but that I doubt it since it's the opposite with most drugs) and everything I've seen indicates they are equalgesic. BUT, one advantage to rectal is that it may provide a longer duration of action; I know one study said rectal oxy lasted twice as long as IV, but with half of the effect, and it took over an hour onset, but at equal doses it lasted much longer(6-9, vs 3-4, for IV I believe). But then most sources say the half-life of oxy is always the same, regardless of MOA(which matches with my experiences). But, I am just trying to come up with some positive!!! But seriously, plugging oxy is kinda silly, it's one if the few opies with a decent(albeit variable) oral ba, and if you fuck up trying to administer it rectally, well, that's a pill your not getting back And since I can't see a tangible benefit, why mess with a good thing???

 

[crOOk]

I'm sorry, but what your saying about rectal oxycodone makes no sense. First off, tmax with rectal dosing is (typically) longer than oral, so peak effects are delayed. And the BA is roughly the same(40-90% on both counts, though rectal might be less erratic, but that I doubt it since it's the opposite with most drugs) and everything I've seen indicates they are equalgesic. BUT, one advantage to rectal is that it may provide a longer duration of action; I know one study said rectal oxy lasted twice as long as IV, but with half of the effect, and it took over an hour onset, but at equal doses it lasted much longer(6-9, vs 3-4, for IV I believe). But then most sources say the half-life of oxy is always the same, regardless of MOA(which matches with my experiences). But, I am just trying to come up with some positive!!! But seriously, plugging oxy is kinda silly, it's one if the few opies with a decent(albeit variable) oral ba, and if you fuck up trying to administer it rectally, well, that's a pill your not getting back And since I can't see a tangible benefit, why mess with a good thing???

Of that is the case, then what I have said about rectal oxycodone use indeed makes no sense (except for how to prepare your pills lol). I was under a misconception there and could swear that the things I said applied for those times when I used it rectally over orally (which I would usually do, whether illicitly or prescribed).

Btw clearance of the drug would remain the same of course, but I really was under the impression that it took less time for the entire amount to enter the blood stream and would therefore reduce the total duration of effects. I guess I was wrong and should edit my post accordingly.

I should have really double checked this before posting!

EDIT: Needless to say I had to doublecheck and everything you said seems correct:

Rectal oxycodone provides effective analgesia for patients who have difficulty swallowing or in whom the oral dosage form is contraindi- cated. Limitations of rectal administration include erratic absorption, limited patient acceptance, and a longer absorption lag time and time to Cmax than oral tablets (Tmax 3.1 hours vs. 1.5 hours).13 This may be the result of poorer blood supply to the rectum and a smaller surface area for drug absorption as compared to the upper gastrointestinal tract. Lo- cal irritation may develop at the absorption site, and an anorectal rash may limit its use after some weeks.13 The bioavailability of rectally ad- ministered oxycodone suppository (47 to 62%) is similar to orally ad- ministered tablets; however, there is large interpatient variation.13,33 This suggests that either there is no significant difference in first-pass effect of oxycodone when administered rectally or there is incomplete absorption from the suppository.

Source: The pharmacokinetics of oxycodone., J Pain Palliat Care Pharmacother. 2004;18(4):17-30.

 

[Lorne???]

Of that is the case, then what I have said about rectal oxycodone use indeed makes no sense (except for how to prepare your pills lol). I was under a misconception there and could swear that the things I said applied for those times when I used it rectally over orally (which I would usually do, whether illicitly or prescribed).

Btw clearance of the drug would remain the same of course, but I really was under the impression that it took less time for the entire amount to enter the blood stream and would therefore reduce the total duration of effects. I guess I was wrong and should edit my post accordingly.

I should have really double checked this before posting!

EDIT: Needless to say I had to doublecheck and everything you said seems correct:

First off, 3.1h to Tmax? Jesus Christ! I knew it was delayed, but that is crazy!!! It is highly variable though, I have seen studies with it ranging from 1.5-2.5h, whereas oral oxy is usually around 90 minutes.

Secondly, thank you for your reply and posting a source!(which is something I should have done). That may seem odd to thank you, but it brings me to:

Thirdly: I would like to clear up the misconception about rectal administration. Or, rather help to clear it up. I don't know why people are under the impression that rectal hits hard and fast, because, generally speaking, it doesn't. You see, rectal is basically akin to sublingual administration. In both cases the substrate is being diffused into membranes, either in under your tongue, or in your rectum. But the drug does not absorb directly into the blood stream; rather it diffuses slowly from the administration site. Now, that's about as far as my knowledge of the mechanics goes, but in both cases, they're is a delayed effect. Imagine sublingual buprenorphine, and how long it takes for it to reach full effect.

But with Oxy, it appears it might actually be longer with rectal. Again, buprenorphine is the perfect example; the half-life of IV bupe is only 2-6h(mean roughly 3.5) yet sublingual is insanely long,(though insanely variable as well) ranging from 12-48, with a mean in the area of 24-30.
Of course it is nothing like that with oxy, but in many cases it appears these two methods if administration yield an extended duration. Of course, as you mentioned, the clearance would be the same I am just looking for some benefit to it!

However, this is not universal, as for example, with Methadone, absorption is much faster rectally, with a rectal Tmax of around 1.5h(can't remember the range) vs. 2.5h for oral(range 1.7-4) and some other drugs with the right chemical properties can be absorbed (somewhat) rapidly, however, for most it will actually have a delayed onset(just like sublingual).

One last thing, I see now you we're not encouraging her to go rectal(that sounds off!) in fact, quite the opposite; you we're just giving her the method. And I must say, your method seems perfect for anyone who simply insists on trying it!!!

 

[crOOk]

I swear I remembered that to be very different, but I really haven't used oxycodone much via that roa. Now that I do think back really hard, I used it intranasally a lot (a roa that I despise) and had disappointing results from rectal use (probably due to the delayed Tmax).

Regarding the rectal administration generally, it can be a lot more efficient and faster than the oral route, this is true for a large number of drugs, among them some opioids. I'd have to check and see, before naming which opioids that are, I'm not making a fool of myself again! :D Some compounds that actually do hit considerably faster would be MXE, MDMA, MDA, methylphenidate and a lot of other phenethylamines. For some substances it is as close to IM/IV use as you can get and the time of onset can decrease massively, e.g. for MDMA where it could take as little as 5-10 minutes vs. 30-45min via the oral ROA (don't quote me on the exact time). Especially MDMA is also subjectively much more intense via the rectal roa. The reasons for why one molecule passes through the rectal membranes so much faster than another are plentiful, an obvious one being that the rectal pH is much higher than in the mouth or nose. I really do not know that much about it, but I can see the amount of fluid being present in the mouth be problematic when it cames to the rate at which the respective substance passes through.

Ok lol I just read the paragraph before the last in your post, so I guess this wasn't needed at all. I personally wasn't aware that there are so many substances for which the absorption rate is actually decreased it had been my understanding that this is only the case for a few exceptions. I guess it simply depends on the chemical being inserted...

EDIT: I looked into a number of opiates now for which I really had been assuming rectal ba and absorption would be higher and faster respectively. In most cases I was simply wrong and looking back I had looked into each of them at one point or another before taking them and had decided to stick to using them orally. My brain is apparently playing tricks on me. However with there being so many phenethylamines that are much more suitable for rectal administration (if the goal is a rapid onset and high peak plasma concentration or a high bioavailability), I am curious to look into what molecular properties generally determine this. I'd suspect molecule size, octanol water partition coefficient and pKs to play a role and I'm optimistic there have been some general "rules" (for lack of a better word) established for this. If you know of any paper discussing it, please do let me know.

 

[Lorne???]

You see, this is why collaboration is so vital! This very moment, I was wondering exactly why methadone was relatively effective rectally(as methadone is one of the most interesting drugs, and a personal face of mine, to use and study) yet the answer was staring me in the face: PH. As you mentioned, it is more favorable down below. As I'm sure you know, most(if not all) opioids are weak bases, but methadone is especially alkaline. Indeed, what you probably didn't know, is that methadone's absorbtion/excretion is so dependent upon PH, that it actually(dramatically) effects half-life. Check it out: a modest increase in urine PH greatly increases half-life, and increases the amount of free methadone in blood. Basic urine gives an average half-life which is double, or even triple that with acidic!

Ok, I am rambling, just saying, it's nice to see someone with similar interest to mine. I can tell your more knowledgeable, though. I honestly don't know much about other drugs; my interest lies almost exclusively with my beloved opioids, which I find simply fascinating. However, I have also studied the benzodiazepines, and in regards to rectal admin, the result is the same, though they're is far less data on using benzo's by other moa's, and in any case, the properties of benzo's wouldn't lend them well to rectal.

But yeah, I know with some drugs rectal is very effective, (I actually know people who have plugged MDMA) it just depends on the specific drug. But in general, it lends itself to delayed absorbtion, with rapid being the exception. My concern is with regard to opioids, they're are so many posts through the years on Blue light, with people saying ( it is almost as intense as IV" which simply isn't true, especially with not with opioids, which tend to absorb rather erratically. I just wish there was some way to correct all that misinformation, like a disclaimer or something, though I am probably taking it too far.

But anyway, I have countless studies bookmarked, and several of them discuss rectal, but, alas, everything I have deals with opioids. By all means, if you find a good paper on the mechanics of it, pass it along!

(And more thing, and maybe I'll quit detailing this thread. And this isn't to you CrOok, but anyone else reading, I am not against rectal administration of drugs, at all, it's just that when it comes to opioids, even the few where rectal is effective(methadone and diamorphine, come to mind) it is still less effective than intranasal, and nowhere near IV(though a helluva lit safer!) if people choose to do it, fine, but they should have the facts, which simply don't seem to be well known around the community. Crook is no fool,he knows what the hell he is talking about, so this just shows how widespread this myth is. Ok, rant over!

Let's just try to get the truth out their, people!