1. Predicting intestinal and hepatic first-pass metabolism of orally administered testosterone 3 undecanoate 4
- Author
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Zgair, Atheer, Dawood, Yousaf, Ibrahim, Suhaib M, Back, Hyun-Moon, Kagan, Leonid, Lee, Jong Bong, and Gershkovich, Pavel
- Subjects
first-pass metabolism ,human liver ,Testosterone undecanoate ,bioavailability - Abstract
The bioavailability of orally administered drugs could be impacted by intestinal and 12 hepatic first-pass metabolism. Testosterone undecanoate (TU), an orally administered ester prodrug 13 of testosterone, is significantly subjected to first-pass metabolism. Yet, the individual contribution 14 of intestinal and hepatic first-pass metabolism is not well determined. Therefore, the aim of the 15 current study was to predict the contribution of each site. The hydrolysis-time profiles of TU 16 incubation in human liver microsomes and Caco-2 cell homogenate were used to predict hepatic 17 and intestinal first-pass metabolism, respectively. The in vitro half-life (t1/2 inv) for the hydrolysis of 18 TU in microsomal mixtures was 28.31 ± 3.51 min. By applying the "well-stirred" model, the fraction 19 of TU that could escape hepatic first-pass metabolism (FH) was predicted as 0.915 ± 0.009. The 20 incubation of TU in Caco-2 cell homogenate yielded t1/2 inv of 109.28 ± 21.42 min which was applied 21 in "Q gut" model to estimate the fraction of TU that would escape intestinal first-pass metabolism 22 (FG) as 0.114 ± 0.02. Accordingly, only 11% of the absorbed fraction of TU could escape intestinal 23 metabolism while 91% of which can pass hepatic metabolism. Hence, compared to the liver, the 24 intestinal wall is the main site where TU is significantly metabolised during first-pass effect. 25
- Published
- 2020