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.

中文翻译：

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预测口服十一酸睾酮的肠道和肝脏首过代谢

口服药物的生物利用度可能受到肠道和肝脏首过代谢的影响。十一酸睾酮 (TU) 是一种口服给药的睾酮酯前药，明显受到首过代谢的影响。然而，肠道和肝脏首过代谢的个体贡献尚未确定。因此，当前研究的目的是预测每个位点的代谢贡献。TU 在人肝微粒体和 Caco-2 细胞匀浆中孵育的水解时间曲线分别用于预测肝脏和肠道首过代谢。TU 在微粒体混合物中水解的体外半衰期 (t1/2 inv) 为 28.31 ± 3.51 分钟。通过应用“充分搅拌”模型，可以逃避肝脏首过代谢 (FH) 的 TU 分数预计为 0.915 ± 0.009。TU 在 Caco-2 细胞匀浆中的孵育产生 109.28 ± 21.42 分钟的 t1/2 inv，将其应用于“Q 肠道”模型以估计 TU 的比例，该比例将逃避肠道首过代谢 (FG) 为 0.114 ± 0.02。因此，只有 11% 的 TU 吸收部分可以逃脱肠道代谢，而 91% 可以通过肝脏代谢。因此，与肝脏相比，肠壁是 TU 在首过效应期间显着代谢的主要部位。因此，只有 11% 的 TU 吸收部分可以逃脱肠道代谢，而 91% 可以通过肝脏代谢。因此，与肝脏相比，肠壁是 TU 在首过效应期间显着代谢的主要部位。因此，只有 11% 的 TU 吸收部分可以逃脱肠道代谢，而 91% 可以通过肝脏代谢。因此，与肝脏相比，肠壁是 TU 在首过效应期间显着代谢的主要部位。