The Pharmacology and Metabolism of Testosterone Undecanoate (Tu), a New Orally Active Androgen

Abstract

Testosterone undecanoate (TU), either dissolved in arachis oil or as micro-crystal suspension, displays androgenic activity on oral administration to rats in the Hershberger test. The solution in arachis oil is more active than the crystal suspension. When [3H]TU is administered orally to rats, most of it is metabolized in the intestinal wall. The majority of the metabolites probably lose their undecanoate group and are absorbed via the portal vein. The non-metabolized [3H]TU and at least two metabolites are absorbed exclusively via the lymphatic system. One of these metabolites has been identified as 5\g=a\-dihydrotestosterone undecanoate (5\g=a\-DHTU).TU has no harmful effects on the liver of the rabbits on oral administration.It is well known that testosterone is inactive in man on oral administration (Foss 8c Camb 1939) while the widely used orally active androgen methyltestosterone may cause hepatic dysfunction in man: BSP retention (deLorimier et al f965) and jaundice (Werner et al. 1950; Foss 8c Simpson 1959). Foss 8c Simpson (1959) showed that testosterone propionate had no effect on liver function in man on parenteral administration. The present study describes the androgenic activity in rats, the effect on liver function in rabbits and the meta¬ bolism in rats of a new orally active androgen, testosterone undecanoate.

Lymphatic Transport of Methylnortestosterone Undecanoate (MU) and the Bioavailability of Methylnortestosterone Are Highly Sensitive to the Mass of Coadministered Lipid after Oral Administration of MU

“…After perfusion of an MU emulsion through an isolated section of jejunum in anesthetized rats, the concentrations of MU in blood draining the perfused intestinal segment were below the limits of quantification at all the time points, whereas appearance of M was clearly evident (data not shown). This finding confirmed that a significant proportion of the presystemic conversion of MU to M occurred in the enterocyte, consistent with previous reports for TU (Coert et al, 1975;Horst et al, 1976). Unpublished investigations have also shown that plasma esterases play a negligible role in the hydrolysis of MU and that hydrolysis by hepatic esterases is considerably more avid (data on file, Schering Plough).…”

“…The use of prodrugs is one approach that has been used successfully to increase the oral bioavailability of highly metabolized compounds (Stella et al, 2007). In the case of testosterone, previous studies have shown that oral administration of testosterone esters may be used to facilitate effective testosterone exposure (Coert et al, 1975;Noguchi et al, 1985), and an oral formulation for the administration of testosterone undecanoate (TU) (Andriol Testocaps; Schering Plough, Kenilworth, NJ) is currently marketed in several countries. The bioavailability of testosterone after oral administration of TU is low and predominantly attributable to lymphatic transport of the lipophilic ester prodrug followed by postabsorptive cleavage to release the active testosterone .…”

Lipid-Based Drug Carriers for Prodrugs to Enhance Drug Delivery

“…This process can be advantageous from a PK perspective, since absorption into the lymph system rather than portal blood bypasses the liver and avoids first-pass metabolism (22). This benefit is exploited for several drugs, such as orally administered testosterone (testosterone undecanoate prodrug) (47)(48)(49), that are ineffective due to their extensive first-pass metabolism. Alternatively, from a drug targeting perspective, preferential absorption into the lymphatic system can be used to target drugs to treat lymphatic cancers (50,51) and is also important for antiviral medication for protection of B and T lymphocytes (52)(53)(54).…”

“…The simplest form of the three, lipophilic esters/ethers, also has the most limited success. The results often show that the extensive pre-absorptive hydrolysis circumvents lymphatic transport; however, some success has been noted for delivery of highly potent hormone drugs such as testosterone (48,49,55). In strategies utilizing glycerides to enhance lymphatic transport, the site of drug attachment to the glyceride is an important consideration.…”

Síndrome de insuficiência androgênica: critérios diagnósticos e terapêuticos

“…Apregoa-se que o seu efeito hepático possa ser menor que o da metiltestosterona, visto que, após a absorção intestinal, sofre um desvio do sistema porta e se dirige ao ducto toráxico. Esse caminho para chegar ao sangue através da veia subclávia se dá pelo fato de possuir uma cadeia alifática e ser transportada na linfa junto com os lipídios (Coert et al, 1975).…”