madman
Super Moderator
Abstract: The bioavailability of orally administered drugs could be impacted by intestinal and hepatic first-pass metabolism. Testosterone undecanoate (TU), an orally administered ester prodrug of testosterone, is significantly subjected to the first-pass metabolism. However, the individual contribution of intestinal and hepatic first-pass metabolism is not well determined. Therefore, the aim of the current study was to predict the metabolic contribution of each site. The hydrolysis–time profiles of TU incubation in human liver microsomes and Caco-2 cell homogenate were used to predict hepatic and intestinal first-pass metabolism, respectively. The in vitro half-life (t1/2 inv) for the hydrolysis of TU in microsomal mixtures was 28.31 ± 3.51 min. By applying the “well-stirred” model, the fraction of TU that could escape hepatic first-pass metabolism (FH) was predicted as 0.915 ± 0.009. The incubation of TU in Caco-2 cell homogenate yielded t1/2 inv of 109.28 ± 21.42 min, which was applied in a “Q gut” model to estimate the fraction of TU that would escape intestinal first-pass metabolism (FG) as 0.114 ± 0.02. Accordingly, only 11% of the absorbed fraction of TU could escape intestinal metabolism, while 91% can pass through hepatic metabolism. Hence, compared to the liver, the intestinal wall is the main site where TU is significantly metabolized during the first-pass effect.
1. Introduction
Testosterone undecanoate (TU, Figure 1) is an ester prodrug of the anabolic steroid, testosterone. TU was introduced in the late 1970s as an effective oral testosterone replacement therapy [1,2]. In fact, testosterone is well absorbed from the intestinal lumen. However, therapeutic plasma levels following oral administration of testosterone cannot be achieved due to extensive first-pass metabolism [3]. Therefore, TU and other testosterone prodrugs have been proposed to reach effective levels of testosterone by avoiding pre-systemic metabolism and/or to provide more flexible therapeutic options in terms of the route of administration, and stability of plasma levels attained [4]. Once absorbed into the systemic circulation, the undecanoate side chain of TU is cleaved by the action of non-specific plasma esterase to release testosterone [5]. Currently, TU is commercially available as oral capsules, Andriol Testocaps® and Jatenzo®, and intramuscular injections, Aveed® and Nebido®. These formulations commonly used in the treatment of male hypogonadal disorders characterized by low serum levels of testosterone.
5. Conclusions
In conclusion, compared to the liver, the intestinal wall is the major site where the absorbed fraction of TU is extensively metabolized. It seems that intestinal lymphatic transport can decrease the exposure of TU to intestinal hydrolyzing enzymes as well as circumventing hepatic first-pass metabolism. However, further studies are required to explore the metabolism of TU in vivo. Furthermore, the authors recommend investigating the impact of using an intestinal enzyme-inhibitor on the bioavailability of oral TU. Moreover, it appears that Caco-2 cell homogenate can be used to predict the intestinal first-pass metabolism of particular ester prodrugs.
1. Introduction
Testosterone undecanoate (TU, Figure 1) is an ester prodrug of the anabolic steroid, testosterone. TU was introduced in the late 1970s as an effective oral testosterone replacement therapy [1,2]. In fact, testosterone is well absorbed from the intestinal lumen. However, therapeutic plasma levels following oral administration of testosterone cannot be achieved due to extensive first-pass metabolism [3]. Therefore, TU and other testosterone prodrugs have been proposed to reach effective levels of testosterone by avoiding pre-systemic metabolism and/or to provide more flexible therapeutic options in terms of the route of administration, and stability of plasma levels attained [4]. Once absorbed into the systemic circulation, the undecanoate side chain of TU is cleaved by the action of non-specific plasma esterase to release testosterone [5]. Currently, TU is commercially available as oral capsules, Andriol Testocaps® and Jatenzo®, and intramuscular injections, Aveed® and Nebido®. These formulations commonly used in the treatment of male hypogonadal disorders characterized by low serum levels of testosterone.
5. Conclusions
In conclusion, compared to the liver, the intestinal wall is the major site where the absorbed fraction of TU is extensively metabolized. It seems that intestinal lymphatic transport can decrease the exposure of TU to intestinal hydrolyzing enzymes as well as circumventing hepatic first-pass metabolism. However, further studies are required to explore the metabolism of TU in vivo. Furthermore, the authors recommend investigating the impact of using an intestinal enzyme-inhibitor on the bioavailability of oral TU. Moreover, it appears that Caco-2 cell homogenate can be used to predict the intestinal first-pass metabolism of particular ester prodrugs.
