In a study of the absorption and delivery of (anticancer) medication in the human body, Teun van Herwaarden, a researcher at the Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital (NKI-AVL), examined the detoxifying effect of the Cytochrome P450 3A (CYP3A) enzymes. This group of enzymes metabolises toxic substances found in foodstuffs and consequently, many types of medicine.
By comparing different mice, van Herwaarden clarified the impact of CYP3A on metabolism. The researcher also measured the degree to which CYP3A activity in the liver as opposed to the intestine is actively involved in blocking absorption of the medication. This useful model is a help in developing more specific, easily absorbed medicines.
How many medicines are blocked?
The CYP3A detoxification system leaps into action in more than half of the medicines currently used. In their body, each individual possesses different amounts of the group of enzymes that break down toxic substances and, therefore, various anticancer medicines. This often makes it difficult to predict just how much of the medication that is primarily broken down by CYP3A a patient will absorb, thus affecting the efficacy of the medicine.
In this research project, funded by Dutch technology foundation STW, at the Netherlands Cancer Institute–Antoni van Leeuwenhoek Hospital, Van Herwaarden bred mice without CYP3A. The metabolism of medicine in these mice was compared to that of those possessing CYP3A (normal mice). This pinpointed the influence of CYP3A on metabolism. Van Herwaarden also analysed mice whose liver cells had been adapted to produce human CYP3A to test the amount of medication that was metabolised. He did the same with mice whose intestinal cells had been modified to produce human CYP3A. This data allowed him to measure where, and in which quantities, the medicine was metabolised.
Wide application
The animal model developed by Van Herwaarden can aid in developing a medicine that is less toxic and enters the body more easily through the liver and intestine. It can also be used to assess possible interactions with other medication. The animal model is suitable for the development of a wide range of medicines. The companies taking part in this project are expected to start using the mouse models that have been generated.
Graduation Teun van Herwaarden, June 12, 2007, University of Amsterdam
Promotor: Prof. dr. P. Borst
Co promotor: Dr. A.H. Schinkel
Source: STW