Pharmacokinetics & Injection Volume  

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ready2explode
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08/07/2019 5:53 pm  

Jb suggested we started another thread, so here it is!

My contention is that half life remains the same regardless of concentration as long as the total dose is the same. This was shown in the minto study, although the authors recommend caution when extrapolating to other types of oils.

http://jpet.aspetjournals.org/cgi/content/full/281/1/93

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ready2explode
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08/07/2019 6:10 pm  

The minto study refers to this paper, stating that the esters are absorbed faster than the oil itself.

Tanaka, T., Kobayashi, H., Okamura, K., Muranishi, S. and Sezaki, H.: Intramuscular absorption of drugs from oily solutions in the rat. Chem. Pharm. Bull. (Tokyo) 22: 1275-1284, 1974

Sadly, I do not have access to this study and it is not online. So, if anyone could track it down, it would be nice.

I am of the belief that the body rapidly absorbs the esters from the depot site. Thus, it wouldn't matter how large the site is, at least not significantly.

"In any contest between power and patience, bet on patience."
~W.B. Prescott

"Only two things are infinite, the universe and human stupidity, and I'm not sure about the former."
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ready2explode
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08/07/2019 6:31 pm  

For those that don't completely comprehend the concept, here is an example I copied off the net:

Example: You have a 10ml container of orange squash. You put this into a litre (ok 990ml!) of water. The Vd of the orange squash is 1000ml. If, each minute, you empty 10ml of the orange liquid into the 10ml container, discard this, and replace it with 10ml of water. The clearance is 10 ml per minute. The elimination half life is: 70 minutes . The kel is Cl/Vd = 10/1000 = 0.01. Shown the other way, 0.693/50 = 0.01.

If the volume of the container is increased to 2000ml, then the clearance remains the same, but the Vd, and consequently the t1/2, increases (to 140 minutes).

This was taken from this site: http://www.4um.com/tutorial/science/pharmak.htm

My girl is bitchin' that dinner is ready...I'll be back... LOL

"In any contest between power and patience, bet on patience."
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"Only two things are infinite, the universe and human stupidity, and I'm not sure about the former."
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jboldman
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08/07/2019 6:51 pm  

i need to research this more thoroughly but i would think htat he partition coefficient is relativelylow due to the insolubility of the esters in water. lets go some of you research guys, start looking for studies, one would think that this has been studied to death.

jb


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ready2explode
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08/07/2019 7:16 pm  

http://jcem.endojournals.org/cgi/content/full/90/5/2624

Nandrolone 50, 100, 150mg injection...volume was constant

Half life 50mgs - 7.1 days
Half life 100mgs - 11.7
Half Life 150mgs - 11.8

Looks to me like it might matter at lower doses, but not higher. Will continue searching.

"In any contest between power and patience, bet on patience."
~W.B. Prescott

"Only two things are infinite, the universe and human stupidity, and I'm not sure about the former."
~Albert Einstein


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ready2explode
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08/07/2019 7:40 pm  

http://www.andrologyjournal.org/cgi/reprint/19/6/761

500mgs vs 1000mgs (250mg/ml)

No statistical difference in terminal half life. I am making the assumption that the 4mls of test were shot in 1 injection. The full text dose not specify.

"In any contest between power and patience, bet on patience."
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"Only two things are infinite, the universe and human stupidity, and I'm not sure about the former."
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Andy13
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08/07/2019 7:56 pm  
Posted by: ready2explode
The minto study refers to this paper, stating that the esters are absorbed faster than the oil itself.

I am of the belief that the body rapidly absorbs the esters from the depot site. Thus, it wouldn't matter how large the site is, at least not significantly.

The partition coefficient for the esters is necessarily greater than the oil it is dissolved in. Otherwise, the oil would be partitioned into the blood leaving behind insoluble ester. The ester half life depends on this.

Once ester partitions from the depot, it is rapidly hydrolized, so the oil, in essence, protects the ester from hydrolysis.

The rate of enzymatic hydrolysis of all esters is essentially identical. It is not the affinity of the ester for the esterase enzyme that confers ester half life, but rather, the parition coefficient of the ester in oil. A generalization (though not entirely correct) is that the greater the solubility in oil, the greater the partition coefficient.

In theory, the partition coefficient of the ester is independent of its concentration in oil.


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ready2explode
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08/07/2019 8:19 pm  

I was hoping you'd chime in, Andy. How do you dismiss the findings above? Do you believe that there is a certain concentration where pharmacokinetics begin to change?

In other words, give me some more info. I am certainly no expert in this area.

This seems to be a problem in my mind, "Otherwise, the oil would be partitioned into the blood leaving behind insoluble ester. The ester half life depends on this."

If this were the case, then how can you dismiss the use of long acting esters such as undecanoate when single injections lead to half lives that must be longer than it took for the oil to be absorbed from the depot site. How about in the studies above where 50mgs in 1ml of oil had a significantly shorter half life than 100mgs in 1ml of oil? One would think that the half life would be the same or longer because of the protection provided by the oil...

"In any contest between power and patience, bet on patience."
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"Only two things are infinite, the universe and human stupidity, and I'm not sure about the former."
~Albert Einstein


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Black Baccara
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08/07/2019 8:47 pm  
Posted by: ready2explode
http://jcem.endojournals.org/cgi/content/full/90/5/262 4" target="_blank" rel="noopener"> http://jcem.endojournals.org/cgi/content/full/90/5/2624

Nandrolone 50, 100, 150mg injection...volume was constant

Half life 50mgs - 7.1 days
Half life 100mgs - 11.7
Half Life 150mgs - 11.8

Looks to me like it might matter at lower doses, but not higher. Will continue searching.

It is not perfectly clear if the volume was the same for all doses.
It is written :"Subjects were randomized and treated with a single im dose in the gluteal muscle of nandrolone decanoate in 1 ml arachis oil (Deca-Durabolin, Organon International, Inc., Roseland, NJ)."
If they've used labeled Deca-Durabolin, as far as I know it does not exist in 150mg/1ml, only 50mg/1ml or 100mg/1ml.
After in the study they always speak about a single IM injection but never speak again about volume considerations.


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Andy13
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08/07/2019 9:04 pm  
Posted by: ready2explode
This seems to be a problem in my mind, "Otherwise, the oil would be partitioned into the blood leaving behind insoluble ester. The ester half life depends on this."

If this were the case, then how can you dismiss the use of long acting esters such as undecanoate when single injections lead to half lives that must be longer than it took for the oil to be absorbed from the depot site.

Do you have a ref for this? How do we know the oil is absorbed from the depot site before the ester?

As I eluded to earlier, the release of the ester from the depot does not occur with (and as a function of) the oil absorption. If that were the case, all esters would have the same half life.


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ready2explode
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08/07/2019 9:27 pm  
Posted by: Black Baccara
It is not perfectly clear if the volume was the same for all doses.
It is written :"Subjects were randomized and treated with a single im dose in the gluteal muscle of nandrolone decanoate in 1 ml arachis oil (Deca-Durabolin, Organon International, Inc., Roseland, NJ)."
If they've used labeled Deca-Durabolin, as far as I know it does not exist in 150mg/1ml, only 50mg/1ml or 100mg/1ml.
After in the study they always speak about a single IM injection but never speak again about volume considerations.

Ya missed something, BB. Here's a quote from the study, "It was decided to keep the injection volume constant and increase the dose of nandrolone decanoate by increasing the concentration. As a consequence, the effects of dose and concentration cannot be separated statistically."

"In any contest between power and patience, bet on patience."
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"Only two things are infinite, the universe and human stupidity, and I'm not sure about the former."
~Albert Einstein


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ready2explode
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08/07/2019 9:55 pm  
Posted by: Andy13
Do you have a ref for this? How do we know the oil is absorbed from the depot site before the ester?


No ref, just seemed logical when half lifes are approaching 2 weeks +.

"In any contest between power and patience, bet on patience."
~W.B. Prescott

"Only two things are infinite, the universe and human stupidity, and I'm not sure about the former."
~Albert Einstein


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Andy13
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08/07/2019 10:14 pm  
Posted by: ready2explode
How about in the studies above where 50mgs in 1ml of oil had a significantly shorter half life than 100mgs in 1ml of oil? One would think that the half life would be the same or longer because of the protection provided by the oil...

It's hard to say. We're talking about two different things.. One is ester half life, the other is serum half life of nandrolone. The latter is what is measured in the papers.

If you were to construct an in vitro model using 50mg and 100mg in 1ml oil inside a stirring beaker of water containing esterase, the half lifes of the esters would be same. It gets complicated when we use serum nandrolone levels to draw conclusions about ester depot kinetics. There are countless factors that would cause the different half lives.. such as binding to proteins and metabolism.


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ready2explode
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08/07/2019 10:35 pm  

Hmmmm, more to ponder over...

"In any contest between power and patience, bet on patience."
~W.B. Prescott

"Only two things are infinite, the universe and human stupidity, and I'm not sure about the former."
~Albert Einstein


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jboldman
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08/07/2019 11:01 pm  

it is clear that some oils allow partitioning out of the esters slower than others, eg castor oil. it sounds as if the higher the concentration of ester/ml the slower the partiioning out (not intuitive) i would also think that the larger the volume of oil the slower the partioning would be. there have to be studies examining this.

btw, nice to see you on the boards andy.

jb


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