Unlocking safer medicines: “Redefining Microsome Use in Drug Metabolism”

The Problem

How do we know drugs are safe for humans to use during drug development? An essential step is understanding how they interact with the liver and kidneys.

When you take a medicine, enzymes in the liver are crucial. This is because they determine things like how easily your body can flush the drug out through the kidneys. Known as drug metabolism, this process is key to ensuring medicines are not only effective but also safe.

Currently, scientists rely on liver microsomes. These microsomes are taken from animals, primarily rats, to study the intricate drug metabolism process. Liver microsomes carry all the essential liver enzymes so using them allows researchers to study how:

A drug behaves when it’s taken.

Spotting potential problems early on, like unintended side-effects.

While it’s tricky to get an exact figure, some estimates suggest that as many as 27 rats might be needed for each new drug compound being developed. This reliance on animal-derived ingredients raises more than ethical issues. It’s also costly and can offer inconsistent results.

The need for a new method is clear.

That’s where fungi come into the picture. Fungi, such as Cunninghamella elegans, offer a promising alternative. These fungi are capable of producing enzymes similar to those in our own livers.

What makes them such an exciting replacement option?

They’re easy to produce and grow, which could reduce research costs.

They can be engineered to produce specific human enzymes. This helps improve their relevance for drug metabolism research.

They could replace the use of rats entirely, making them a more ethical option.

The Project

Agata will explore how well these fungal-derived microsomes can replace their rat-derived counterparts.

She plans to grow custom-built fungal systems that produce key human enzymes involved in drug processing. Next, Agata will test them using the Drug-Bank database to cross-reference their performance against existing data from animal liver microsomes.

To ensure these fungal-derived microsomes can be produced in greater quantity for widespread use, she’ll investigate methods to consistently and efficiently grow them. She’ll test them in small petri dishes all the way to larger 96-well plates.

To study how well the fungal systems can predict how drugs interact with each other, she’ll use liquid chromatography-mass spectrometry. This sophisticated technology acts like a super-sensitive detective, identifying and measuring tiny molecules and will help her track how drugs are transformed.

This will help her determine if these fungal systems can accurately predict how different drugs might interact with each other, which is a key safety concern when giving drugs to patients.

The Potential

If Agata’s research goes to plan, she hopes to demonstrate that these fungal-derived microsomes are not just a good alternative, but a reliable and cost-effective one.

Imagine a future where drug development is more efficient, more precise, and significantly reduces the need for animal testing. This innovative approach could truly revolutionise how we bring new, safer medicines to people, benefiting everyone in the long run.

The update

Agata set out to test whether the fungus Cunninghamella elegans could be used as a model to predict how drugs may be broken down safely in the human liver. If the fungus metabolised known drugs in a similar and predictable manner, then it could potentially be used as a replacement for the current method of using animal liver-derived microsomes.

During her project, she successfully grew the fungus in the lab and incubated it with a variety of well-known drugs, including caffeine and ibuprofen, as a test panel to see how the fungus would break them down.

The data she generated using the liquid chromatography-mass spectrometry (LC-MS) suggested that some of the drugs were indeed broken down into the molecules that were predicted from human data, showing that there is value in developing this early research further.

However, with other drugs, it wasn’t quite so straightforward to tell. Research often generates just as many questions as it answers, and Agata’s project was definitely one of these occasions!

In her report, Agata has made some very insightful suggestions about how these issues might be resolved, including changing incubation conditions, adjusting LC-MS detection, and even using a different, and better known, species of fungus.