article on AAS esters
by Bill Roberts
Building the Perfect Beast by Author L Rea - This book is a discussion of advanced muscle chemistry techniques utilized by some of the top bodybuilders. The characters portrayed are purely fictional beings created as a means of re-telling a tale from many individuals whom have chosen the chemically enhanced path in competitive sports. Any resemblance to a certain pro-bodybuilder or his “trainer” currently tearing up the competition world is merely coincidence. The following is a discussion of how some current competitive beasts were built. Anabolics 2004: Anabolic Steroid Reference Manual - The best selling and most highly regarded drug reference book in history! Now in its third update and fifth year of printing, no book even comes close to the depth and accuracy of information provided in this one. Inside this oversized 400+ page manual Llewellyn shares well over a decade's worth of meticulous medical research and real-world experience, bringing the reader a combination of scientific knowledge and personal insight unparalleled by any writer in the field.
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Publication Date: December 13, 1999
Nothing in this article is intended to take the place of advice from a licensed health professional. Consult a physician before taking any medication.
Injectable anabolic steroids are usually available as esters of the parent drugs. Often, a drug in its original form may lack certain properties that are desired: for example, good solubility in oil or fat. There may be a part of the molecule to which one may add an additional chemical group to give the new molecule desired properties, but in such a way that over time in the body, the modification will be removed, restoring the parent drug. If the modified molecule is itself not active, needing to be converted back to the parent drug, then this is a prodrug. Anabolic steroids such as testosterone cypionate and nandrolone decanoate are prodrugs. Since esters of anabolic steroids are so often used in bodybuilding, in this article we will examine them closely.
At a particular position (#17) all anabolic steroids have a hydroxy group, consisting of an oxygen and hydrogen, represented by OH. This can be replaced by an ester group: for example, propionate (OOCCH2CH3). This results in improvement in solubility in oil and reduction of water solubility, both of which are useful for reasons later to be discussed.
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How do esters differ in structure?
While quite an array of names exist and make the issue seem complicated, the main difference between different esters is simply the number of carbon atoms in the ester. Propionate, as shown above, has three carbons, whereas acetate has two, isobutyrate has four, enanthate has seven, cypionate has eight, and decanoate has ten. On occasion there are more unusual esters, such as cyclohexylmethylcarbonate (used in Parabolan) which has eight carbons and one more oxygen than the above esters do.
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How do esters change the physical properties of steroids?
Testosterone, nandrolone, and other anabolic steroids have poor solubility in either water or oil. Esterifying them improves oil solubility. This enables useful dosages of perhaps 100 mg or more per cc. But the more carbons the ester has, the lower the water solubility becomes, and the higher the partition coefficient (ratio between lipid and water solubilities) becomes. If the partition coefficient is high, then at any moment a high proportion of the prodrug is dissolved in oil or body fat, and only a small proportion is dissolved in water.
This is important. If testosterone itself is given in oil solution, it transfers too easily from oil to the water in the blood. The result is that an oil injection of testosterone gives a sudden spike in testosterone levels, which rapidly drops. Injections would be required at least twice per day, and perhaps even more often. Improving the oil solubility and decreasing the water solubility slows this transfer, and extends the half-life of the drug to several days or more.
The number of carbons also has a small effect in that it reduces the parent drug’s proportion of the total weight. E.g., it would take 344 mg of testosterone propionate, or 401 mg of testosterone enanthate to give the same amount of testosterone as in 288 mg of testosterone suspension.
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How are esters converted back to the parent drug?
The ester bond is fairly easily broken under the right conditions. If the molecule is dissolved in water, this can occur by a simple chemical reaction, yielding the parent drug and a carboxylic acid. For example, if the steroid used is testosterone propionate, testosterone and propionic acid are released. Carboxylic acids are safe and natural in the body in reasonable amounts. It should not be thought that these are strong acids because they are not: they are acids in the same sense that, e.g., Vitamin C or lactic acid are acids. Furthermore, the amount of carboxylic acid present at any time is extremely low.
The carboxylic acids do not have any activities of interest. Once the ester group is removed, it has done its job, and the parent drug acts in its normal manner.
Besides the simple chemical hydrolysis described above, the esters can be removed by enzymes in the blood called esterases, though water still is required for the reaction. The great majority of hydrolysis occurs with the help of these enzymes or by non-specific reactions with proteins. These reaction cannot take place while the esterified steroid is dissolved in fat. Thus, while the esterified steroids are dissolved in fat, they are protected from hydrolyis, and thus serve as a depot for the drug, giving extended duration of action.
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What is the significance of the partition coefficient?
Differences in partition coefficient seem to account almost fully for the differences between various esters of anabolic steroids, as shown by Chaudry and James.1,2 To understand their work, though, it is necessary first to consider the methods they used to obtain their data on the anabolic and androgenic effects of the drugs tested.
These scientists are not using those terms in the manner which many bodybuilding authors do. The anabolic effect is measured by increase in weight of the levator ani muscle in the rat, and the androgenic effect is measured by increase in weight of the seminal vesicles and prostate. These measurements are neither perfectly indicative of muscle-building value to bodybuilders nor to any particular undesired side effect except perhaps prostate enlargement. Despite the limitations of the method, this was the assay method available.
A number of esters of nandrolone were studied, using various single doses, but only the results from a single dose of 1 mg are given here. The results are as follows:
Parent Drug
Ester
# of Carbons
Anabolic Effect
Anabolic / Androgenic Ratio PRC** (P) x10-3
Nandrolone formate 1 1176 13:1 15*
acetate 2 1594 11:1 25*
propionate 3 1880 10:1 41*
butyrate 4 1488 7:1 69
valerate 5 2526 9:1 115*
hexanoate 6 3731 9:1 192
heptanoate 7 6559 13:1 269
octanoate 8 5557 15:1 611
nonanoate 9 5080 19:1 455
decanoate 10 7735 25:1 802
undecanoate 11 6576 32:1 1460
*extrapolated from P of the butyrate ester
** partition ratio coefficient
The anabolic effect was found to be predictable according to the equation:
log (anabolic effect) = 7.33 log P – 0.636 log P2 –17.8
The accuracy of predictions was quite high (r = 0.970) and the F value, indicating the statistical significance of the equation, was very high at 61. Thus, the observed anabolic effect of these ester prodrugs of nandrolone was found to be highly correlated with partition coefficient.
Higher partition coefficients were also strongly correlated with higher anabolic/androgenic ratio.
It was also found that the times of first and second peaks of drug level after injection were predictable from P with good accuracy and high significance.
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7. Belkien, L.; Schurmeyer, T.; et al. J. Steroid Biochem., 1985, 22, 623-629
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