Transport and metabolism of azol antifungal drugs in the human term placenta

Bjarne Styrishave

Drugs are the group of chemicals that modern humans are by far most widely exposed to. Unfortunately, several drugs have the capacity to disrupt the endocrine system in humans unintentionally, for example by decreasing the production of sex steroids. The group of drugs known as azole fungicides is among the most endocrine disrupting drugs on the Danish marked. These drugs are first-line of treatment for fungal infections and are also widely used in pregnant women due to vulvovaginal candidiasis, infecting around 20% of all pregnant women.

The balance between male and female sex hormones during pregnancy is crucial for fetal development and significant efforts are made to investigate effects of drugs used during pregnancy on fetal sex development. Traditionally, these experiments are made with animals, most often pregnant mice as surrogate species. These animal studies suffer from two major drawbacks. First, the number of animals needed to conduct these experiments may be very high. 

Secondly, data from such experiments may be difficult to extrapolate to human conditions due to differences in transport of drugs in the placenta from mother to fetus and due to differences in sex steroid metabolism. For example, the human placenta is able to transform male sex steroids into female sex steroids, but the mice placenta is unable to do this. Consequently, the methods currently used to study effects of drugs on fetal development not only require a high number of experimental animals, but the relevance of the data obtained may be very limited for human pregnancies.

The present study funded by the Danish 3R Center proposes an alternative approach in which the human term placenta is used to study the transport and metabolism of azole antifungal drugs and sex steroids between mother and fetus. After giving birth to the placenta, both the maternal and the fetal circulation are reestablished. When azole antifungal drugs are added to the maternal circulation, the transport to fetal circulation, and the metabolism of azole antifungal drugs and sex hormones in the placenta can be analysed.
This approach will completely remove the need for conducting animal experiments, and at the same time provide data of high relevance to human pregnancies. The project will provide new information about azole antifungal drugs as endocrine disruptors and transport and effects during pregnancy. This, in turn, may lead to improved drug formulations and treatment regimes.

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