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

Applied Sciences

SuhaibM. Ibrahem¹  Atheer Zgair¹  Yousaf Dawood¹  Leonid Kagan²  Hyun-moon Back²  Pavel Gershkovich³  JongBong Lee³ 

[1] College of Pharmacy, University of Anbar, Ramadi 31001, Iraq;Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA;School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, UK;

关键词: testosterone undecanoate;    first-pass metabolism;    bioavailability;    human liver microsomes;    Caco-2 cells;   

DOI  :  10.3390/app10207283

来源: DOAJ

【 摘 要 】

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 (t_{1/2 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 (F_H) was predicted as 0.915 ± 0.009. The incubation of TU in Caco-2 cell homogenate yielded t_{1/2 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 (F_G) 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.

【 授权许可】

Unknown