A Potential New Drug for Endometriosis?

Canadian researchers characterized the pharmacological behavior of the steroid derivative PBRM.

Key Points

Highlights:

• Researchers analyzed in detail the pharmaceutical behavior of the steroid derivative PBRM using a mouse model.

Importance:

• Being a blocker of an enzyme that is known to be involved in the development of breast cancer and endometriosis, PBRM could potentially be a new emerging drug to treat these life-threatening diseases,

Key results:

• The sole metabolite of PBRM was PBRM-O, which did not have any estrogenic activity, and which inhibited the 17β-HSD1 enzyme as well as PBRM.
• When injected under the skin of the mice, PBRM showed favorable values regarding half-life, absolute bioavailability, distribution volume, and clearance rate.
• After under-the-skin injection, PBRM was observed in the liver, kidney, and gastrointestinal tract of the mice, which gradually decreased and disappeared altogether after 72 hours and did not accumulate in any organs. 
• A high-quality absolute bioavailability value was obtained when PBRM was given to the mice orally suggesting that could potentially be developed into a drug to be taken by mouth daily.
• PBRM was mainly extracted from the body via feces.
• PBRM was well-tolerated by the mice and showed no signs of toxicity.

Limitations of the study:

• It is important to note that this is a very early stage pre-clinical study conducted in an animal model and the results obtained may not be the same in human clinical trials. 

Lay Summary

A steroid derivative called PBRM could be a new emerging drug to treat endometriosis according to a study by Canadian scientists.

In the study that was published in The Journal of Steroid Biochemistry and Molecular Biology, researchers characterized the pharmaceutical behavior of PBRM using a mouse model.

The same team has recently reported the development of PBRM as an inhibitor, or blocker, of an enzyme called 17β-HSD1. This enzyme is overproduced in breast cancer and is responsible for the production of estradiol, the most potent female hormone. It is known that too much estradiol can lead to a number of diseases including breast and endometrial cancer, as well as endometriosis. Therefore blocking the activity of 17β-HSD1 could be a promising approach to treat hormone-dependent cancers and endometriosis. 

In order to study the pharmaceutical behavior of PBRM, and further characterize this potential new drug, the researchers conducted a number of studies both in cells grown in the laboratory and in mouse models.

First, they used human liver cells to evaluate the stability of PBRM. They found that with time PBRM turned into the oxidized form of the molecule called PBRM-O and no other metabolites or waste products were formed. Not only did PBRM-O not have any estrogenic activity, it also inhibited 17β-HSD1 almost as well as PBRM.

Next, the researchers looked at what would happen to PBRM when they injected it under the skin of live mice and how the body of the animals processes the potential drug. They obtained favorable values in terms of half-life, absolute bioavailability, distribution volume, and clearance rate of PBRM. 

When they looked at the distribution of PBRM in the different organs of the animals, the researchers found that PBRM did not accumulate in any organ after 72 hours; six hours after injection PBRM was observed in the liver, kidney, and gastrointestinal tract of the mice, which gradually decreased and disappeared altogether after 72 hours. 

“Overall, the distribution profile of [PBRM] is coherent with simple blood distribution and gastrointestinal excretion, which is favorable for a candidate drug”, the researchers wrote. 

They also gave PBRM to the animals by mouth and saw that a good absolute bioavailability value was obtained. Bioavailability is the degree and rate at which a drug is absorbed by the circulatory system and is an essential measurement tool because it helps determines the correct dosage of a drug. This favorable finding suggests that PBRM could potentially be developed into a drug to be taken by mouth daily.

Finally, the researchers analyzed how PBRM was being extracted from the body of the mice as this represents an important step in the development of new drug candidates. They found that most of PDRM (93 percent) was extracted with the feces, while the remaining seven percent was thrown out with urine. 

PBRM was found to be well-tolerated by the animals without any signs of toxicity. 

“The favorable safety profile of PBRM, even at high doses, should provide an advantageous flexible therapeutic window regarding future efficiency dose optimization studies for either life-threatening diseases such as breast and endometrial cancers, or other chronic diseases, for example, endometriosis,” the authors concluded. 

It is hoped that the safety and tolerability of PBRM will be tested in clinical trials in the future. 

Research Source: https://www.ncbi.nlm.nih.gov/pubmed/29248731