Esterification is a rather critical part of the pharmaceutical industry. It allows for modification of injectable drug’s distribution and metabolism by modifying their fat-solubility aka – lipophilicity (log P) without altering the pharmacology to any notable degree. In cases of very large esters, it also increases oral bioavailability, I will touch on this later.
Hormones in particular make up a substantially significant portion of esterified medicinal products. Think Anabolic Androgenic Steroids (AAS) in the case of TRT and/or performance enhancement, Esterified Estrogens (EE’s) and Esterified Progesterone in female HRT. Other major esterified pharmaceuticals of note are Nitroglycerin which I’m sure everyone has heard of and Penicillin esters (Benzylpenicillin and Penicillin Procaine).
So what are these esters? All you need to know chemically as far as this article goes is it is junction between a carboxylic acid and an alcohol.
Alcohol (R–OH)+Carboxylic Acid (R’–COOH)→Ester (R’–COOR)+Water (H2O)
The Broscience
A very overbearing myth among Juiced “Bros” is that esters modify the half life of the base compound by creating a “tail” (the acid), which gets snipped carbon by carbon until its back to the base compound. Now this does sound appropriate, but this completely overestimates both chemistry and our biology.
The Reality
The actual mechanism is hydrolysis – esterase enzymes separate the esterified compound back into an alcohol (base compound) and an acid.
Ester (R’-COOR)+H2O → Carboxylic Acid (R’-COOH)+Alcohol (R-OH)
This process happens in the blood and in fact if you were to inject even a relatively larger ester, for example testosterone enanthate, intravenously rather than intramuscularly or subcutaneously, its half-life wouldn’t differ much from the base hormone which is about 8h compared to intramuscular injection being about 7 days.
This is due to the large concentration of esterase enzymes, which carry out the breakdown of esters, in blood. So how does this relate to the metabolism? Well, this already invalidates the idea of “nibbling” away at the tail end of the ester. The actual mechanism of half-life elongation is rate limiting of a compound’s absorption path out of a vehicle depot (Usually Oil based due the nature of esterification being increasing fat solubility which inversely means decreased water solubility) into the blood. This happens in several ways:
Vehicle Depot > Interstitial fluid > Blood (Short Ester)
Short Esters usually have pretty low fat solubility which means they do not really have much affinity to stay in the oil phase inside of the oil reservoir and instead they partition into the surrounding interstitial fluid (fluid surrounding the cells) and then blood through the capillaries – relatively fast. Subcutaneous administration for these compounds is of far higher relevance than any long ester compound due to the restricted blood supply. Subcutaneous tissue has about 5-10x smaller blood supply relative to intramuscular tissue, so compounds that have a sufficiently low fat solubility are dependent on the blood supply due to the lack of rate-limiting when leaving the oil phase. Therefore, subcutaneous administration forces their distribution to be enormously prolonged compared to intramuscular where they would not be rate-limited near as much when distributing into the blood from the interstitial fluid.
Vehicle Depot > Interstitial Fluid > Blood/Lymphatic Fluid (Long Ester)
Long esters on the other hand have high fat solubility, this makes them far more restricted in their affinity to diffuse into the interstitial fluid. This rate-limiting renders subcutaneous administration obsolete when compared to short esters due to their diffusion into the interstitial fluid being too slow to be limited by low blood flow. However, while of low relevance when injected, long esters are also absorbed by the lymphatic system due to their high fat solubility. Lymphatic system is a minor pathway when administered through injection due to its very slow flow rate (roughly 600x slower in contrast to blood) as they are intended for slow drainage, not absorption. This contrasts with intestinal lymphatics which have chylomicrons – a lipoprotein meant to uptake fats from the intestinal tract into the bloodstream.
Intestinal Tract > Lymphatic System > Blood (Very Long Esters)
Exceptionally long esters have extraordinary lipophilicity – this makes them uniquely applicable for oral administration. When orally administered with a fatty meal (necessary to not limit uptake), they are too hydrophobic to get absorbed into the portal vein and therefore liver damage is prevented. Simultaneously, its fat solubility is so dominant that it easily incorporates into the dietary fat medium and gets absorbed by the chylomicrons in the intestinal lymphatic system with them. The bioavailability is low, but it lacks the toxicity and local liver androgenicity caused by liver uptake which makes it a viable route. This has been demonstrated with Testosterone Undecanoate. This is not a viable route for the relatively shorter esters due to them lacking the exceptionally high fat solubility. However this route does not increase it’s half life, its akin to intravenous administration or injectable base hormone in this aspect, just with an additional absorption period.
Bonus
Technically the “snipping” of the carbons does happen, just not to the esterified compound. The acid tail of an ester is chemically inert. However after hydrolysis, if the acid used is a fatty acid (for example heptanoic acid of enanthate ester), it will proceed to undergo beta-oxidation in the mitochondria, which shortens the acid chain by 2 carbons every cycle.