Pharmacokinetics of testosterone

The pharmacology of testosterone, an androgen and anabolic steroid (AAS) medication and naturally occurring steroid hormone, concerns its pharmacodynamics, pharmacokinetics, and various routes of administration. Testosterone is a naturally occurring and bioidentical AAS, or an agonist of the androgen receptor, the biological target of androgens like endogenous testosterone and dihydrotestosterone (DHT). Testosterone is used by both men and women and can be taken by a variety of different routes of administration.

Routes of administration

Testosterone can be taken by a variety of different routes of administration. These include oral, buccal, sublingual, intranasal, transdermal (gels, creams, patches, solutions), vaginal (creams, gels, suppositories), rectal (suppositories), by intramuscular or subcutaneous injection (in oil solutions or aqueous suspensions), and as a subcutaneous implant. The pharmacokinetics of testosterone, including its bioavailability, metabolism, biological half-life, and other parameters, differ by route of administration. Likewise, the potency of testosterone, and its local effects in certain tissues, for instance the liver, differ by route of administration as well. In particular, the oral route is subject to a high first-pass effect, which results in high levels of testosterone in the liver and consequent hepatic androgenic effects, as well as low potency due to first-pass metabolism in the intestines and liver into metabolites like dihydrotestosterone and androgen conjugates. Conversely, this is not the case for non-oral routes, which bypass the first pass. Different testosterone routes and dosages can achieve widely varying circulating testosterone levels. For purposes of comparison with normal physiological circumstances, circulating levels of total testosterone in men range from about 250 to 1,100 ng/dL (mean 630 ng/dL) and in women range from about 2 to 50 ng/dL (mean 32 ng/dL). Testosterone levels decline with age in men. In women with polycystic ovary syndrome (PCOS), a condition of androgen excess, testosterone levels are typically around 50 to 80 ng/dL, with a range of about 30 to 140 ng/dL. Total testosterone levels are about 20-fold and free testosterone levels about 40-fold higher in men than in women on average. Similarly, testosterone production is approximately 30 times higher in men than in women.

Oral administration

Oral testosterone Testosterone is well-absorbed but extensively metabolized with oral administration due to the first pass through the intestines and liver. It is rapidly and completely inactivated in men at doses of less than 200 mg. In large doses, such as 200 mg however, significant increases in circulating testosterone levels become apparent. In addition, while a 60 mg dose has no effect on testosterone levels in men, this dose does measurably increase testosterone levels in prepubertal boys and women. The oral bioavailability of testosterone in young women after a single 25 mg dose was found to be 3.6 ± 2.5%. High levels of testosterone are also achieved with a 60 mg dose of oral testosterone in men with liver cirrhosis. These findings are attributed to induction of liver enzymes by testosterone and consequent activation of its own metabolism. Substitution dosages of oral testosterone in men are in the range of 400 to 800 mg/day. Such doses exceed the amount of testosterone produced by the body, which is approximately 7 mg/day, by approximately 100-fold. The elimination half-life of oral testosterone is rapid at about 5 to 7 hours. As a result, it requires administration several times per day in divided doses. Due to its limitations, such as the high doses required and necessity of multiple daily doses, oral testosterone is not used clinically in its unmodified form. Oral testosterone has been studied in combination with a 5α-reductase inhibitor to reduce its first-pass metabolism and improve its bioavailability.

Oral testosterone undecanoate Instead of in its free unesterified form, testosterone is used by oral administration in the form of testosterone undecanoate. Due to the unique chemical properties afforded by its long fatty acid ester chain, this testosterone ester is partially absorbed from the gastrointestinal tract into the lymphatic system, thereby bypassing a portion of first-pass metabolism in the liver and producing measurable increases in testosterone levels at much lower doses than free testosterone. Of oral testosterone undecanoate that reaches circulation, 90 to 100% is transported lymphatically. However, its duration remains short, with an elimination half-life of 1.6 hours and a mean residence time of 3.7 hours. Oral testosterone undecanoate is provided as 40 mg oil-filled capsules and requires administration 2 to 4 times per day (i.e., 80 to 160 mg/day) for substitution in men. It must be taken with food containing at least a moderate or "normal" amount of fat in order to achieve adequate absorption. In addition, there is very high interindividual variability in levels of testosterone with oral testosterone undecanoate. The bioavailability of oral testosterone undecanoate taken with food is 3 to 7%. Inappropriately high levels of testosterone have been observed with 10 to 40 mg/day oral testosterone undecanoate in women. The oral bioavailability of testosterone undecanoate in young women after a single 40 mg dose was found to be 6.8 ± 3.3%. A novel self-emulsifying formulation of oral testosterone undecanoate in 300-mg capsules for use once per day is under development.

First-pass effect and differences Oral testosterone and oral testosterone undecanoate are not hepatotoxic, unlike orally administered 17α-alkylated anabolic steroids such as methyltestosterone and fluoxymesterone but similarly to parenteral routes and forms of bioidentical testosterone like injections.

Buccal administration Testosterone can be used by buccal administration (e.g., brand name Striant).

Sublingual administration Testosterone can be used by sublingual administration. A 10 mg sublingual tablet with the brand name Testoral was previously marketed for use one to four times per day in men.

Inhalational administration Testosterone has been studied by inhalation.

Intranasal administration Testosterone can be used by intranasal administration (e.g., brand name Natesto).

Transdermal administration

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