Looking back at my life exactly five years ago,
-I remember leaving behind my partner and grandmother in Groningen, of whom the latter passed away six months later;
-I remember leaving behind a healthy family in other parts of the Netherlands, which, unfortunately, is not as complete as it was back then;
-I remember leaving the Netherlands without having signed any contract, but a 3-month contract was fortunately awaiting me in Switzerland (which was later on extended for one, four, six, and twenty-four months);
-and I remember the exciting research ideas that inspired me to leave the Netherlands and which convinced me to give up my perfect life in Groningen.
Regarding the latter, I joined a great research group in Geneva in the Spring of 2019 to explore how I could use an innovative analytical technique for studying daily-life exposure to various chemicals, including therapeutic drugs, illicit drugs, and dietary substances. An underlying motivation for my move was that I had become interested in population-based studies on the long-term effects of such exposures. However, I was not that happy with the importance of questionnaires in the corresponding research field.
Because if you ask me how much fruit I eat every day, I will definitely overestimate my fruit consumption, which is something I consider as a good habit. In turn, if you ask me about something I consider as a bad habit, like alcohol consumption, I will probably provide an underestimate. Moreover, I probably do not even know how much fruit and alcohol I consume on a weekly basis, hence any estimate I provide is prone to be wrong. Relying on self-reported information is thus likely not a good idea, at least not based on the assumption that I am not the only one who finds it difficult to provide accurate estimates of exposure statuses. Hence, I reasoned in 2019 that I needed to develop an analytical tool to provide molecular evidence of chemical exposures, notably using bodily fluids like blood, feces, and urine.
In Geneva, I quickly learned about the innovative technique they had developed there, and I subsequently applied it to thousands of human urine samples. These samples were sent to me by my favorite collaborator in Groningen and originated from people who had undergone kidney transplantation. In this clinical context, there were many questions regarding chemical exposures that needed to be answered, most of which related to lifestyle and nutrition. However, when quickly assessing my analytical data after obtaining them, I noticed a couple of analytical signals which almost jumped out off the screen. I thus made it my mission to find out what these signals were, and five years later they are still taking center stage in many of my projects.
In short, the signals I observed turned out to be so-called ‘metabolites’ of therapeutic drugs. Such metabolites are mostly formed in our liver, and their formation is often essential to make sure that a drug does not stay in our body forever. The thing is, many drugs are fat-loving compounds that would, in principle, like to stay in our body. Fortunately, our body is capable of making them a bit more water-loving, which helps in their removal from the body, mostly via our urine and feces.
I need to mention right away that it did not come as a surprise that I encountered these drug metabolites in my data. Actually, a lot is already known about the ‘metabolism’ of each drug, notably because pharmaceutical companies need to elucidate drug metabolism during (commercial) drug development. What is mostly forgotten, however, is that pharmaceutical companies “only” have to elucidate drug metabolism in small-scale studies including around five human volunteers, mostly healthy white males between 18 and 55 years old. These studies are possibly not very representative of the real-world situation of drug use, and one could expect novel drug metabolites to be found when assessing drug metabolism after a drug is approved.
These last sentences bring me to the exciting new domain of ‘real-world drug metabolism sciences’ which I have been shaping in the past five years. Basically, it is not much more than studying drug metabolism in actual patient populations (long) after a drug has received market approval. And yes, the idea behind it is so simple. Still, it represents a domain that has received very little attention over the last decades.
But is such an apparent lack of attention bad? And should we even care about knowing more about how our bodies transforms the chemicals that we are exposed to?
To answer these relevant questions, please think about how your body reacts to a chemical like caffeine? Are you a person who can easily drink a cup of coffee late in the evening or are you someone who switches to decaf in the evening to ensure a proper night’s sleep (just like me)?
This caffeine example highlights one of the beauties of nature, namely that we are all unique human beings with our own unique characteristics, like the rate at which we degrade chemicals like caffeine. When it comes to therapeutic drugs, this rate of degradation can be a determining factor of therapy response. Because,
-maybe you need two pills to get the desired effect if you degrade a drug quickly;
-maybe you need only a half pill if you degrade a drug slowly;
-maybe you need a different drug because you degrade it so fast that it does not work at all;
-or maybe you need a different drug because you do not degrade it at all which could cause toxic reactions?
These types of questions are being asked by many pharmacists on a daily basis, and increasingly, pharmacists can utilize a person’s genetic information to predict the response towards a drug of choice. This practice reflects the field of ‘pharmacogenetics’, which is currently one of the most exciting research areas that aims to realize more personalized drug therapies. This practice furthermore relies heavily on knowledge on how a drug is metabolized – and now you probably feel it coming – and it often uses the drug metabolism insights elucidated by pharmaceutical companies. Indeed, the latter reflects the knowledge that is typically retrieved through studies on healthy volunteers. And indeed, my field of real-world drug metabolism sciences, my pride and joy, connects seamlessly to the field of pharmacogenetics and may hopefully allow for more effective and safer drug use in the (near) future.
As mentioned, at the moment, very little attention is being paid to drug metabolism in real-world populations. However, I hope that this will change after my recent publication (which is freely available and not as complex as many of my other papers, so do check it out here). I will, anyway, continue to do my utmost to further shape the corresponding field with the help of many great collaborators as well as some talented PhD and Master’s students who are currently working on a few quite exciting projects. So stay tuned.
Lastly, I would normally end a blog post like this by thanking the people who supported me in my work, which are actually a lot. This time, however, I want to pay tribute to the late Professor Bob Wilffert, who was a pharmacogenetics expert at the University of Groningen and who sadly passed away in 2021, shortly before his retirement. Professor Wilffert was probably one of the nicest people I have ever met, and I was honored that he was willing to be an official assessor of my PhD thesis in 2018. His work at our institute furthermore paved the way for the function that was created a couple of years ago, which I am currently fulfilling. I feel honored that I can work in his old office every day, and I hope that I can inspire as many people as he did in his impressive career.
analyzed-by-frank.com 