Okay, so you guys are all aware of the 17a-methyl modification to prevent metabolism in steroids on first pass. But I'm willing to bet most of you don't know there are two separate and distinct types of metabolism possible during first pass. Metabolism is broken up into two phases. Phase 1 is where changes like Ketone to Alcohol takes place; phase 2 is where something called conjugation happens. Conjugation is how our body gets things ready for excretion into urine, and usually happens with the
second pass through the liver. In cases where the substrate (Urolithin B) doesnt have a moiety suitable for phase 1 metabolism, it skips phase 1 and goes directly to phase 2, conjugation.
The purpose of conjugation is to take substrates that are largely non-polar, i.e. steroids or Urolithin B, and make them polar so they can be excreted in urine. They do this by attaching a modified sugar or sulfate group to an alcohol or ketone, or similar group. This increases the polarity so they dont get reabsorbed once they are in the filtrate in the urine, which increases their excretion.
Urolithin B is not subject to any extensive phase 1 metabolism, BUT, it is subject to extensive phase 2 metabolism.
Phase-II metabolism limits the antiproliferative activity of urolithins in human colon cancer cells.
https://www.ncbi.nlm.nih.gov/pubmed/24077694
To quote for those who don't want/have time to read the study,
"We also report here, for the first time, the role of ABC transporters and Phase-II metabolism in HT-29 cells as a mechanism of cancer resistance against urolithins due to their conversion to glucuronide conjugates that exerted lower antiproliferative activity"
The underlined portion is key. The limiting factor in the activity of the Urolithins and their multitude of species is their conjugation. The only way to limit exposure to conjugation is to skip the first exposure to it all together. The only way to skip the first exposure is to use a non-oral route, like IM, SC, or TD.
Here, the authors report that while Urolithin B is amazing on paper, the phase 2 exposure nullifies the effects to a point at which they are no longer relevant.
"Therefore, phase-II metabolism limits the antiproliferative, estrogenic, and antiestrogenic activities of dietary polyphenols on BC cells. Likewise, as a call of caution, enthusiasm should be limited for publishing effects that are not physiologically relevant."
https://pubs.acs.org/doi/10.1021/acs.jafc.8b03100
Lastly, the urine excretion. (This study also showed that gut microbiology also deactivates it via phase 2 metablism)
" However, the microbial metabolite 3,8-dihydroxy-6H-dibenzo[b,d]pyran-6-one (urolithin B) conjugated with glucuronic acid was detected [in the urine] along the fractions F3-F5 in all of the subjects, independently of the consumed foodstuff."
https://www.ncbi.nlm.nih.gov/pubmed/15656654
In summary, the effects of Urolithin B are limited due to phase 2 metabolism. Upon oral ingestion, this occurs in (1) gut microbes (2) hepatic first-pass (3) target tissue cells. TD bypasses 2 out of the 3 phase 2 metabolic routes, meaning TD Urolithin B has only one third the exposure to metabolic deactivation as oral Urolithin B.