A Debate with Bill Roberts on Injection Kinetics

[Conciliator]

I wanted to start a new thread specifically for Bill and me to continue the debate that began here. Bill took issue with something I said that was unreferenced. I'd now like to take the opportunity to show that what I said is well supported by numerous references. I'd also like to challenge Bill to stay focused in this argument and to attempt to present even one counter-references.

For reference, the statement I made that Bill took issue with is the following:

With intramuscular injections into oil depots, the rate limiting process is not clearance from the body, but absorption into the body. The body essentially eliminates the drug as fast as it's absorbed. Whereas longer esters have an absorption half life of several days to over a week, the clearance half life of the actual hormone is much, much shorter. When the ester is cleaved and the base hormone is released and enters into circulation, it's half life is usually a matter of hours, depending on serum binding. Since the absorption half life is so much longer, decline of the drug in the body corresponds to the absorption half life.

Bill argued this is not so. He said "I'm sorry but this is totally screwed up." Really Bill? Well here are numerous references that I'd love to see you try to explain away. They demonstrate that what I said is correct and that your contentions are way out of line.

 

[Conciliator]

[ame="http://www.amazon.com/Seminars-General-Adult-Psychiatry-College/dp/1904671446"]Seminars in General Adult Psychiatry (2nd edition)[/ame], pg 253.

Pharmacokinetics of the long-acting depot preparations
The slow release of the active drug contained in depot preparations profoundly affects their pharmacokinetics and they differ from oral drugs in four key respects:
...
2. For orally administered drugs, the rate-limiting step in metabolism, whereas for depot agents it is their rate of absorption. The absorption rate constant for depot drugs may be less than the their elimination rate constant, which is termed a 'flip-flop' pharamacokinetic profile.

Pharmacokinetic Evaluation of Three Different Intramuscular Doses of Nandrolone Decanoate: Analysis of Serum and Urine Samples in Healthy Men -- Bagchus et al. 90 (5): 2624 -- Journal of Clinical Endocrinology & Metabolism

Nandrolone displays so-called flip-flop pharmacokinetics. This means that the ascending phase of the curve represents the disposition of nandrolone, and the descending part of the curve represents the rate-limiting process of release of nandrolone decanoate from the muscle into the general circulation (19). Therefore, the half-life in the descending phase of the curve is an estimate of the absorption half-life rather than the elimination half-life.

Pharmacokinetics and Pharmacodynamics of Nandrolone Esters in Oil Vehicle: Effects of Ester, Injection Site and Injection Volume — JPET

Variations in side-chain ester chemistry are important in the pharmacokinetics of androgen esters in oil vehicle (Behre et al., 1990). Experimental studies suggest that absorption rates are predicted by the oil/water partition coefficients (or hydrophobicity) and that the oil vehicle is absorbed more slowly than the androgen ester (Tanaka et al., 1974).

Table 4 in this last study shows that the absorption half-time of deca injections is much, much longer than the clearance half-time. For example, a 100mg injection in 1ml of oil into the gluteal muscle has an absorption half-time of 7.7 days and a clearance half-time of .34 days. When the delt muscle is used, the absorption half-time is 12 days and the clearance half-time is .25 days.

 

[Conciliator]

[ame="http://www.amazon.com/Fundamentals-Analytical-Toxicology-Robert-Flanagan/dp/0470319356"]Fundamentals of analytical toxicology[/ame], pg 442

16.5.1 Intramuscular depot injection
...
The way in which slow release is rate limiting can be seen from the kinetics of fluphenazine. Following injection of the nonesterfied parent drug, the plasma half-life was 11h, but when the enanthate (heptanoate) was injected, the terminal half-life of fluphenazine was 3.5 d (Figure 16.7)... Clearly the slow release of ester from the injection site makes it appear that the elimination t0.5 is 3.5 d, when in fact it is the absorption t0.5 that is 3.5 f. That is, the rate of absorption is rate limiting and the rate constants ka and k appear to have been exchanged -- this is sometimes referred to 'flip-flop' kinetics, and is the principle behind all SR [rustained release] preparations.

[ame="http://www.amazon.com/Introduction-Pharmacokinetics-Pharmacodynamics-Quantitative-Therapy/dp/0781751497"]Introduction to Pharmacokinetics and Pharmacodynamics: The Quantitative Basis of Drug Therapy[/ame], pg 113-114

Absorption is Rate Limiting
Occasionally, absorption half-life is longer than elimination half-life, and Case C prevails (Fig. 6-5). The peak concentration occurs later yet and is lower than in the two previous cases, reflecting the slower absorption process. Again, during the rise to the peak, the rate of elimination increases and eventually, at the peak equals the rate of absorption. However, in contrast to the previous situation, absorption is now so slow that considerable drug remains to be absorbed well beyond the peak time. Furthermore, at all times most of the drug is either at the absorption site or has been eliminated; little is ever in the body. In fact, during the decline phase, drug is eliminated virlUally as fast as it is absorbed. Absorption is now the rate-limiting step. Under these circumstances, since the rate of elimination essentially matches the rate of absorption
...
That is, the half-life of decline of the drug in the body now corresponds to the absorption half-life. Flip-lfop is a common descriptor for this kinetic sitaution. When it occurs, the terms absorption phase and elimination phase for the regions where the plasma concentration-time curve rises and falls, respectively, are clearly misleading.

[ame="http://www.amazon.com/Sustained-Release-Injectable-Products-Judy-Senior/dp/1574911015"]Sustained-Release Injectable Products[/ame], pg 84

Factors Influencing Drug Absorption from Oil Solutions and Suspensions
...
A high affinity of the drug for the oil means a slower rate of partitioning of the drug from the formulation into the aqueous interstitual fluid at the injection site and, hence, a slower absorption rate and a longer depot effect. Hirano et al. (1981) found a direct correlation between the experimental partition coefficient of drug measured in vitro and the in vivo absorption rate constant (Table 5.3).

 

[Conciliator]

[ame="http://www.amazon.com/Applied-Pharmacokinetics-Pharmacodynamics-Principles-Therapeutic/dp/0781744318"]Applied Pharmacokinetics and Pharmacodynamics: Principles of Therapeutic Drug Monitoring[/ame], pg 816

Formulation of depot typical antipsychotics involves the esterfication of the active drug (e.g. haloperidol) a long-chain fatty acid (e.g. decanoate), and the resultant compound is dissolved in vegetable oil (e.g. seseme oil). The absorption rate of these agents is slower than their elimination rate constant; this, depot antipsychotics exhibit "flip-flop" kinetics in which the time to reach steady state becomes a function of the absorption rate, and the concentration at a steady state (Cpss) is a function of the elimination rate.33

Progress in Drug Metabolism, Volume 13, pg 155

The parent drug (e.g. fluphenazine, clopenthixol and flupenthixol) is esterfied at the hydroxyl group by long-chain fatty acids to give esters such as enanthates and decanoates. These esters are dissolved in vegetable oils and administed intramuscularly, and can thus be given on a weekly or monthly basis. Since drug availability is essentially controlled by release from the depot (Dreyfus et al., 1976), the value of the absoption-rate constant can be less than that for the elimination-rate constant, giving rise to 'flop-flop' kinetics with an apparently increased elimination half-life.

 

[Conciliator]

Your turn Bill

 

[Stretch]

You can't even beat me in an argument. You gotta defeat all contenders before you move on for the title shot.

Go hug your picture of Arnold instead.

JUST KIDDING!!!

I'm very interested to watch this

opcorn:opcorn:opcorn:

 

[Bigkarch]

what are you trying to prove and give too our community...or are you just wanting to win an argument...

 

[buddy1]

I bet he kicked ass on the debate team in high school....Or....Maybe he sucked and he's trying to make up for it.

 

[IronCore]

He must be waiting on Netflix to get his next Arnold movie in...

No but seriously... what are you saying here? T-esters are slowly released over the given time or... they are not released at all until the given time... at which point they last about .34 days?

therefore a 100mg shot of deca does nothing for a week then its gone in half a day? hardly sounds right to me Gov...

 

[newbie23]

I always thought their was a sharp peak-then a slow decline.

 

[Stretch]

I wanted to start a new thread specifically for Bill and me to continue the debate that began here. Bill took issue with something I said that was unreferenced. I'd now like to take the opportunity to show that what I said is well supported by numerous references. I'd also like to challenge Bill to stay focused in this argument and to attempt to present even one counter-references.

For reference, the statement I made that Bill took issue with is the following:

Bill argued this is not so. He said "I'm sorry but this is totally screwed up." Really Bill? Well here are numerous references that I'd love to see you try to explain away. They demonstrate that what I said is correct and that your contentions are way out of line.

Conciliator.

I'd like to respectfully suggest that you post in VERY PLAIN WORDS, the argument that you are trying to make. This will greatly increase the benefit to the board. Rather than two people arguing over things that the average poster cannot begin to understand. I know I don't understand what the practical application is.

 

[pigeonhed]

I do prefer when people reference things they are talking about. This is all well over my head to be honest but it is nice seeing something with some depth to it on the board. I would like to learn more about these issues although I prefer shorter acting drugs because needles don't really bother me.

Who knows my wife may be wrong and I may actually learn something at some point

God Bless,

Walter

 

[BBC3]

Spunky aint he.........

You went an awful long way to create an argument in the other thread to which had already been agreed to, for the most part. You made it a point to ignore the subject at hand in order to find a hair to split, when we were in tha barber shop all along!!!! Are you sure you are not just running in circles because you have felt the "sting" of that spankin so much that you now enjoy it???

Well perhaps now that you have created your own personally custom taylored game, to which I am sure you have the blueprints to all the secret escape doors, you are more than ready. It would just seem that you are in this for the sole purpose of debate.

And thats fine by me, as the "AssHat" appears to fit the original manufacturer very well. I do not appreciate you jackin my thread as a means to challenge Bill. You data is appreciated, just clearly misguided.

Well, let your games continue as you know I am patiently waiting to swoop in and "pop that little bubble" you live in at the first opportunity. May you get yur hiney spanked again.....!!!![)]

 

[BBC3]

I will hijack in the name of easing the tension..... I would also like to relate some of the real issues I was after.....

Conci, I will give you these are some interesting studies. They would seem to debunk, or diminish my concernes with the onset of the release for these type esters. To some degee. After very briefly reviewing these first two articles, I WOULD LIKE TO POINT OUT, that one of my concerns goes unaddressed. These two studies are boased on only one injection. I would like to know what happens after repeated injections to a single muscle group. Do you have any on this.? For example:

(1) At what point does the esterfied drug start to saturate into heavy "off-site" adipose tissue. Meaning, at what time does pinning one's right buttock, does the oil begin to leach out toward the fat of his ass. This will prove to be a completely different release rate.
(2) By what means does the esterfied steroid disperse beyond the immediate muscle. Can it travel via blood stream to fat in other areas? Is it only local at best if at all?
(3) If local only, is the time that the ester can move away from the immediate muscle limited to the amount of time the BB will sustain the increased solubility?
(4) Or would excess injections simply saturate immediately into general circulation via capillary action? If so, how do circulating fat levels act in this process, and if if heavy and constant enough, does this provide for a vehicle to travel to perhiperal areas elsewhere, muscle or fat.?
(5) I also think that the BB should not be discounted for these purposes. Clearly the role of the BB is to provide for solubility while the injection disperses, so when you begin to deal with this real scenario of saturation of a muscle group, it could perhaps be in play to a larger extent, and depending on its type of bond with the ester. I am suspicious that the BB gives the ester extra ability to enter general circulation from a saturated muscle, especially the first two days it remains effective. Does it? Could it also provide protection in the blood stream to deliver the ester to remote locations?
(6) Clearly muscles will saturate soon after a first few 400mg injections. So what gives? Can you offer some proof of what is happening here?
(7) You also have to consider these same muscles may also be saturated with Tcyp esters in real application and may be saturated for starters, if not fairly immediately. Something has to occur here. Something other than the scope of those studies encompasses?

There is no question that these two studies only partially apply in real application due to saturation. So where is the excess going? My point still stands, that with long term esters actually comes periods of great excess, waste, and ogran strain.... My concept of "release date" will apply moreso to esters than manage to find heavy adipose tissue, aka "deep fat".... Clearly as a muscle group could saturate quickly in real application, if the excess does indeed have a strong propensity to find immediate adipose tissue, rather than distant muscle, a real issue with a fatty buildup occurs thus changing the game completely. I have not double that the release of even a decanoate ester can start occuring from muscle related fat, as initially, it will go into "active fat" at best....

These two studies provide nothing more than a theoretical BASELINE for a representation of the mechanics of the ester action is a "PERFECT SCENARIO". I would hazzard to guess that all bets are off even after as little as 500 mgs to a single muscle group..

I would like to play, if you will play nice...

Seminars in General Adult Psychiatry (2nd edition), pg 253.


Pharmacokinetic Evaluation of Three Different Intramuscular Doses of Nandrolone Decanoate: Analysis of Serum and Urine Samples in Healthy Men -- Bagchus et al. 90 (5): 2624 -- Journal of Clinical Endocrinology & Metabolism


Pharmacokinetics and Pharmacodynamics of Nandrolone Esters in Oil Vehicle: Effects of Ester, Injection Site and Injection Volume — JPET
Table 4 in this last study shows that the absorption half-time of deca injections is much, much longer than the clearance half-time. For example, a 100mg injection in 1ml of oil into the gluteal muscle has an absorption half-time of 7.7 days and a clearance half-time of .34 days. When the delt muscle is used, the absorption half-time is 12 days and the clearance half-time is .25 days.

 

[BBC3]

Finally, your use of the term "absorption" is loose in appearance. Do you mean absorption into fat, or absorption into the system once the ester is broken and the S is released from fat.???. I am assuming you are talking about absorption into general circulation as the ester is removed.... Absorption sounds like initial uptake to fat on injection. I believe this is the problem here.

You would appear to be taking Bill's apples and Throwing oranges at him...? Bill never said the limiting rate was not the fact that the ester is hung in FAT. He said that in METABOLISM it is indeed. IT WOULD APPEAR AS IF YOU ARE TRYING TO PUT INCORRECT WORDS IN HIS MOUTH FOR THE SAKE OF DEFEATING HIM!!! You state he has said something he did not say and then argue??

I think the problem lies in the fact that some use of the term absorption as a desciption of the release of the ester into the bloodstream, is confusing. I would assume that term to be associated with the uptake INTO THE FAT. YOU ARE AGRUING WITH YOURSELF. Not only, you have chosen a batten that did not even need to be fought. You should have understood the miscommunication. WHAT, is it a simple admission that Bill did not recognize the use of the term absorption as used as a redistrobution into general circulation POST ester release that you are looking for? You had to know this.... And then you make 5 or 6 certations of the principle that is already given?

This is what I am talking about. It is almost iMPOSSIBLE to communicate with you... It would appear that not only do you embrace a good debate ( and you may very well be introverted to a level that you are truely not aware of meaning beyond strick definition), but you are simply searching too hard for the argument.

WHY DONT YOU TRY FULLY ENGAGING IN THE TOPIC FROM A FULLY READ AND POSITIVE STANDPOINT. YOU WILL FIND MORE THAN ENOUGH OPPORTUNITY TO PROVIDE FOR CORRECTNESS FROM THAT POSITION????????

AND DONT PULL THE "DIFFUSION CARD", as we are not living on a page of Black's Law Dictionary in real life.....

 

[BBC3]

And FURTHER AND FINALLY FROM ME.( Till you get off you tiny little ass and play).

I am further gathering that Bill simply said that you are wrong to assume that blood serum concentration can not limit metabolism. As per any given drug, and specifically based on the molecular weight of such, relatively speaking, the saturation levels of the drug in the blood CAN limit the re-infusion process. Simply put, if the blood is full, it is full. And the faster it burns through it, the more quickly it can handle more.

And Finally, HE STATED THIS IS NOT THE CASE WITH LONG STEROID ESTERS. AND THAT THE ESTER IS INDEED TO PRIMARY FACTOR. HE JUST SAID YOUR STATEMENT WAS WRONG. HE DID NOT SAY IT WAS DUE TO THIS PARTICULAR ASSOCIATION. He states that the active circulating steroid gets metabolized very quickly. A lot quicker than the ester releases. Period.

SUMMARY: He stated what you posted 4,6, or whatever articles citing. The ester is the limiting fator. He also simply stated you were wrong to say the blood concentrations could not be a primary limiter.

Am I missing something.?

YOU CAN STUBBORNLY SIT BACK AND REFUSE TO ACKNOWLEDGE ANYONE'S POST AS A CHILDISH PROTEST TO BILL NOT RESPONDING TO YOUR CHALLENGE IF YOU WANT. But perhaps if you would show the slightest attempts to explain and help people, rather than pick isolated contexts to attack, he would be more forthcomming toward you. After all, it was he who stated he would not participate in your attempts at arguing for the sake of. So what was the purpose of this whole thread when he already said what you spent three post to prove what he said?? You should be more open to helping, by participating POSITIVELY, and perhaps he would want to play with you too. He has nothing to prove to you. You should be so fortunate to interact. YOUR SOLE INTENTION WOULD APPEAR TO BE ARGUMENTATIVE. You are confusing people.... There is only NEGATIVE VALUE in that....

 

[Stretch]

I'm sure BR will respond soon enough.

And I'm interested in watching this once it gets going.

 

[Conciliator]

what are you trying to prove

Seriously? Did you read the thread or any of the references? I'm trying to prove that my quote in the first post is true.

or are you just wanting to win an argument...

A forum, by definition, is a medium for an exchange of views. So when I present a view and Bill Roberts jumps in and says it's "totally screwed up," I think I have every reason to defend what I said.

 

[Conciliator]

No but seriously... what are you saying here? T-esters are slowly released over the given time or... they are not released at all until the given time... at which point they last about .34 days?

The former. I'm saying that esterfied steroids are slowly released over time. In the case of deca that you refer to, I'm saying half the drug leaves the injection site every 7.7 days. And once out of the injection site and in circulation in the body, half of the drug will be cleared from the body every 0.34 days. So it slowly leaves the injection site and doesn't last long once it's out of the injection site.

therefore a 100mg shot of deca does nothing for a week then its gone in half a day? hardly sounds right to me Gov...

Doesn't sound right to me either. I wasn't saying this.

 

[Conciliator]

Conciliator.

I'd like to respectfully suggest that you post in VERY PLAIN WORDS, the argument that you are trying to make. This will greatly increase the benefit to the board. Rather than two people arguing over things that the average poster cannot begin to understand. I know I don't understand what the practical application is.

I'll give it a shot. Let's start by looking at a graph of blood levels of testosterone after an injection of 200mg of test cyp.

Embedded image is unavailable

Just as newbie said, there's a sharp peak and then a slow decline. The statement I made (and that Bill disagreed with) has to do with the following question: what is causing the decline? What does the decline represent? Is it the body slowly breaking down and eliminating the test that's in circulation? Or is it the test still being absorbed by the body, but at a slower and slower rate?

For most drugs, levels in the body rise as the drug gets absorbed. For example, if you take an oral steroid, the steroid is absorbed from the GI tract fairly quickly. The entire absorption phase takes only a few hours. In other words, all of the oral steroid is digested and ends up in circulation in a matter of hours (in accordance with its bioavailability). As the drug is being absorbed, blood levels get higher and higher until they reach a peak. The phase where blood levels are increasing (until the peak) is called the absorption phase. As we know, the body processes drugs, like the oral steroid. The liver and other enzymes in the body break it down and metabolize it. As that happens, levels in the body decline (from the peak), until essentially all of the oral steroid is gone and there is none in the blood. The phase where blood levels are dropping after the peak is called the elimination phase.

OK. That's a typical case. Based on this model, if we look at the chart above for test cyp, we might think that levels in the body rise as all of the test enters the body's circulation. We might think that the absorption phase represents all of the test being absorbed into the body. We might also think that decline of the drug, during the elimination phase, is due to the body slowly breaking it down and metabolizing it. This is the important point. Although we might think that and it might appear to be the case, it's NOT.

So what's really happening then? When you inject an steroid, you're creating what's called a "depot" in the muscle. In common usage, a depot is a storage place, right? When you inject a steroid and create an "oil depot" in muscle, you're creating what is essentially a steroid storage place. Unlike what we might have thought above, all the steroid does not quickly enter into circulation. It's not quickly absorbed at all. Instead, it stays in the depot. The steroid leaves the depot , enters circulation, and gets absorbed into the body relatively slowly. The longer the ester is, the more slowly it leaves the depot. That's because the depot consists of oil (fat) and the longer the ester is, the more lipophilic, or "fat-loving" it is. An important feature of a depot is that release of the drug follows a half-life. That means the steroid doesn't leave at a constant rate, but it leaves slower and slower as time goes on. For example, if we had a depot containing 200mg of test cyp, the first 100mg might leave the depot and get absorbed into the body in the first 3 days. In the next 3 days, 50mg might leave. In the next 3 days, 25mg might leave. And so on. This would represent a 3-day half-life of absorption. Every 3 days, half of the steroid leaves the depot and gets absorbed by the body.

So what does it represent here when blood levels of the drug decline during the elimination phase? As I said earlier, we might mistakenly believe it's due to the body slowly breaking down and metabolizing all the test we injected. But in fact, it represents absorption of the drug from the depot. The reason blood levels are declining is actually due to the fact that the amount being absorbed by the body is slowly decreasing, due to the half-life I explained above. The decline doesn't represent the rate at which the body is breaking down, or clearing the drug at all, but rather the rate at which it's slowly absorbing it! This is called 'flip-flop' kinetics. What we see in the "elimination phase" (as levels drop from the peak) actually represents not clearance or elimination from the body, but the rate of absorption into the body,

I think that pretty much sums it up. If there was anything I said or terminology I used that wasn't entirely clear, let me know and I can try to clarify it.

I'll end by quoting what I said one more time. It should hopefully make a lot more sense now:

Usually when people talk about the biological half life, they're referring to the clearance or elimination half life. That's because most drugs are quickly absorbed (usually orally, from the GI tract) and decline of the drug in the body is determined primarily from the elimination or "disposition," which is rate limiting. With intramuscular injections into oil depots, the rate limiting process is not clearance from the body, but absorption into the body. The body essentially eliminates the drug as fast as it's absorbed. Whereas longer esters have an absorption half life of several days to over a week, the clearance half life of the actual hormone is much, much shorter. When the ester is cleaved and the base hormone is released and enters into circulation, it's half life is usually a matter of hours, depending on serum binding. Since the absorption half life is so much longer, decline of the drug in the body corresponds to the absorption half life.