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Message: <blockquote data-quote="madman" data-source="post: 217459" data-attributes="member: 13851">You are not understanding the PK.It is dosed twice daily.Even then there is no issue with liver toxicity.[URL unfurl="true"]https://www.excelmale.com/forum/threads/jatenzo-an-oral-testosterone-replacement-therapy.20514/[/URL]Figure 2: Mean (±SEM) Concentration-Time Profile for NaF-EDTA Plasma Total Testosterone in <a href="https://www.excelmale.com/forum/threads/fda-approves-new-oral-testosterone-capsule-called-jatenzo.18173/" target="_blank">JATENZO</a> Treated Subjects at Final PK Visit[ATTACH=full]19734[/ATTACH][ATTACH=full]19733[/ATTACH][URL unfurl="true"]https://www.excelmale.com/forum/threads/jatenzo%C2%AE-challenges-in-the-development-of-oral-testosterone.24093/[/URL]*PHARMACOLOGY OF ORAL TESTOSTERONE THERAPYOral administration of exogenous TT historically has proven to be unsuccessful. Despite adequate absorption in the gastrointestinal system, this form of testosterone undergoes extensive first-pass metabolism through the liver, and thus requires ingestion of supraphysiological doses to attain therapeutic serum levels [14]. As a way to circumvent the liver metabolism pathway, research efforts to administer oral testosterone have taken two primary paths: alkylation of testosterone at the carbon-17 position and fatty-acid esterification of testosterone to create a testosterone ester (Fig. 1).Alkylation of testosterone at carbon 17α results in 17αmethyltestosterone which allows for the ability to bypass the first metabolism in the liver. However, this modification has been linked to significant liver toxicity including cholestasis, hepatitis, and hepatic adenocarcinoma [15–17] and lowering of HDL cholesterol [18, 19]. The effects of methyltestosterone on liver function were first described in the 1940s, with studies of liver function demonstrating elevations in both serum direct and indirect bilirubin levels [19]. Foss and Simpson also described a case series of 42 patients who developed jaundice during methyltestosterone therapy [20]. They noted that the duration of therapy to the onset of jaundice ranged from 8 days to 10 months and withdrawal of methyltestosterone therapy resulted in remission of hepatocellular dysfunction within a few days to weeks. Recent work has focused on testing the effects of synthetic androgens on liver function utilizing animal models [21] and has corroborated prior work demonstrating direct increases in alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, and sorbitol dehydrogenase. Therefore, methyltestosterone is largely not recommended for the management of male hypogonadism [6, 22].Esterification of testosterone at carbon 17β yields testosterone esters such as testosterone cypionate, testosterone propionate, and testosterone undecanoate (TU). Specifically for TU, this modification allows testosterone to be absorbed via the lymphatic system and therefore bypass liver degradation. An early oral TU formulation (ANDRIOL®) was approved for use in many countries but never in the United States. This formulation is heavily reliant on dietary fat intake as a means of increasing absorption and therefore leads to significant intra- and inter-patient variability in testosterone response [23, 24]. This results in the need to dose hypogonadal men with several capsules three or more times daily affecting compliance. Several studies have also demonstrated both gastrointestinal and liver adverse effects including severe cholestasis and jaundice [25, 26]. Consequently, these oral TU formulations have never been widely utilized to treat TD in the United States although they remain available in many countries</blockquote>

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