Why does a medicine work well for one person, but cause side effects in another? Research by Laura de Jong shows that it's not just our DNA that matters - other medicines and illnesses can also affect how our bodies respond.
The goal of De Jong's PhD research was to predict how someone will react to a medicine, so that treatments can be tailored more effectively. This fits within the broader idea of personalised medicine. While it's long been known that our DNA plays a role in how quickly we break down certain drugs, De Jong focused on non-genetic factors - such as co-medication and inflammation.
That's because even people with the same DNA profile can respond very differently to the same medicine. 'We wanted to understand why one person's liver breaks down a drug more slowly than another's,' De Jong says. 'That affects how much of the drug ends up in your bloodstream, and how well you tolerate it.'
Her conclusion: to really predict how well someone's liver breaks down a medicine, you have to look beyond their DNA. A patient's overall health and any other medicines also play a major role. Only when you consider all these factors, you can get a full picture of how well the liver is functioning at that moment.
When medicines and genetics interact
De Jong looked at how certain medicines can slow down or speed up liver metabolism. For example, omeprazole (a common acid reducer) moderately inhibits a liver enzyme, while fluvoxamine (an antidepressant) is a strong inhibitor. 'If you already have a genetic variant that slows down that enzyme, and then take a medicine that further blocks it, the drug stays in your system much longer,' she explains. That increases the risk of side effects.
For her research, she used liver biopsies from forty patients. 'We saw clear differences between DNA profiles. But what's still missing in treatment guidelines is the combined effect of genetics and co-medication.' And that's the challenge: although we know a lot about drug interactions and about genetics, this knowledge is rarely brought together. 'This research is a first step towards a more integrated approach.'
What happens to the liver during inflammation?
Inflammation also affects how the liver works. That could be due to an acute infection like COVID-19, or a chronic condition such as rheumatoid arthritis. In the lab, De Jong mimicked inflammation in human liver cells to see how different enzymes responded.
'Some enzymes turned out to be much more sensitive to inflammation than others,' she says. 'That's important, because if the liver is temporarily less active, that needs to be taken into account when prescribing medicines.' At the moment, there are no official guidelines on how to adjust doses for patients with inflammation. 'The first step is raising awareness among doctors that illness can affect liver function - something that's often overlooked.'
Interestingly, liver function partly recovers when the inflammation is treated with anti-inflammatory drugs. 'We wrote a systematic review to identify which of these drugs help restore liver capacity, and which don't,' De Jong says. 'The ultimate goal is to match the medicine dose even more precisely to a patient's current state of health.'
'When it finally works, it's all the more rewarding'
De Jong was the first PhD student supervised by Martijn Manson in this project, which meant she had to do a lot of pioneering and figure things out as she went. 'That was challenging at times, but I had a lot of freedom to follow my curiosity. And when it all comes together, it's incredibly satisfying.'
PhD defence
Laura de Jong received her PhD cum laude on 5 June for her thesis 'The impact of non-genetic factors on drug metabolism: towards better phenotype predictions'. Her PhD supervisors were Robert Rissmann, Jesse Swen and Martijn Manson.
