Predicting Intestinal and Hepatic First-Pass Metabolism of Orally Administered Testosterone Undecanoate

Atheer Zgair,Jong Bong Lee,Suhaib M Ibrahem,Pavel Gershkovich,Hyun-Moon Back,Yousaf Dawood,Leonid Kagan

doi:10.3390/app10207283

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 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 metabolised during first-pass effect.

Highlights

IntroductionTestosterone undecanoate (TU, Figure 1) is an ester prodrug of the anabolic steroid, testosterone
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]
First-pass metabolism is not limited to the liver, It is generally accepted that first-pass metabolism is a significant impediment to the the major site of metabolism, but other organs and tissues are involved, such as the gastrointestinal bioavailability of many orally administered drugs

Summary

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]. Testosterone is well absorbed from the intestinal lumen. Therapeutic plasma levels following oral administration of testosterone cannot be achieved due to extensive first-pass metabolism [3]. 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 to the systemic circulation, the undecanoate side chain of TU is cleaved by the action of non-specific plasma esterase to release testosterone [5].

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