Highly commendable that you have a reference!
I don’t have free access now to the full article and would rather not pay for it simply to get to it sooner, but here’s the abstract anyway:[i]
J Clin Endocrinol Metab. 1985 Oct;61(4):705-10.
Bioavailability of albumin-bound testosterone.
Manni A, Pardridge WM, Cefalu W, Nisula BC, Bardin CW, Santner SJ, Santen RJ.
Abstract
The unbound fraction of plasma testosterone (T) can freely enter tissues, whereas the bioavailability of the albumin-bound T is controversial. A clinical observation in hirsute women receiving spironolactone suggested an experimental paradigm to test the effect of albumin binding on T bioavailability. We found an increase in the non-T-estrogen-binding globulin-bound fraction of plasma T in women from 24.1 +/- 3.9% to 42.0 +/- 8.1% (+/-SEM) while they received spironolactone. Computer modeling indicated that the absolute increase in the albumin-bound T concentration would be about 22.4-fold greater than that in the unbound T concentration (the ratio of albumin-bound to free T remaining virtually constant) because of the binding of T to albumin. We reasoned that the addition of graded amounts of spironolactone and its metabolites to plasma would provide a means to increase the albumin-bound T concentration appreciably. We evaluated the biological effects of this perturbation of T transport by spironolactone and its metabolites in a bioassay system using the Oldendorf technique. Bioavailable T increased proportionately with increments in free and albumin-bound T (r = 0.85; P less than 0.01). A major portion of the albumin-bound T (i.e. 55%) entered tissues under all conditions; the amount that was bioavailable vastly exceeded the amount of T that was unbound in the injected samples. An index of the amount of bioavailable T can be determined using the ammonium sulfate precipitation technique, as the percentage of non-T-estrogen-binding globulin-bound T in vitro correlated well with T bioavailability in vitro (r = 0.86; P less than 0.01). These studies support the conclusion that albumin-bound T is biologically important.[/i]
So far as I know the Oldendorf technique measures permeability, not biological activity at all in any way, as for example a reporter gene assay would do, or measurement of any in vivo biological effect would do something towards.
From the abstract there’s no indication that a different intracellular free testosterone concentration was achieved due to this permeability difference (over time I’d expect equilibrium in free T between extracellular and intracellular, as permeability is fairly good and testosterone is not consumed within the cells by interaction with the androgen receptor, and rate of conversion to metabolites is relatively low).
So it sounds to me like they found what they were looking for, but weren’t looking for anything that actually shows more androgen receptor activity or actual biological effect.
Again not to be repetitive but what’s known about receptor binding and activity, any kind of receptor, all the molecular pharmacology in this regard is based on concentration of free agonist. Amount bound is simply a function resulting from the amount of binding material together with the free concentration.
Where binding material can be especially important is where having a binding protein that changes conformation according to pH; in this instance, a xenobiotic can be picked up systemically where free concentration might be relatively low and the binding might be such that an extremely high proportion will in equilibrium be be bound rather than free, and when brought to the liver, this constant is dfiferent due to the different conformation, and a large percentage frees from the protein, resulting in locally higher free concentration in the liver and more rapid metabolic elimination. Different subject than here, and doesn’t make more serum albumin result in more biological activity of testosterone, but mentioned for the sake of not making it sound as if protein binding is always irrelevant to drug metabolism.
Another important reason is for effective distribution from point of absorption or production to the rest of the body. Here, testosterone has extremely low water solubility, and if there were no protein binding, I don’t know that it could be effectively transported from the testes given the amount of blood flow and the rate of production. With SHBG, however, the amount produced is easily transported as fast as it is produced. Again for completeness, but not causing higher serum albumin to make testosterone do more.
Basically it seems to me, from the abstract anyway, that they’re asserting by definition (or accepted asserted definition of others) that testosterone bound to serum albumin is “bioavailable,” and found that mass transport of testosterone was higher with more albumin, but did nothing to show more activity.
On the same logic, I could call testosterone dissolved in bodyfat “bioavailable” too. It most certainly will be used by the body sometime, it is available biologically to the organism as it transfers to aqueous phase, which it absolutely does all the time, in equilibrium. However, knowing the total amount dissolved in bodyfat does absolutely nothing towards aiding our knowledge of how much will happen biologically. That will be from the free testosterone.