The aim of this project is reduce uncertainties in effect assessment in humans following exposure to designer drugs. Studying differences in metabolism, drug transport and target organ susceptibility of designer drugs will lead to a better exposure-effect assessment.

The influence of phase I, phase II and phase III metabolism on designer drug induced toxicity will be studied in vitro. Metabolism will be studied in human hepatic THLE cells transfected with single CYP450s. Studies on drug transporters (phase III) will be performed on co-cultures of intestine and hepatic cell lines. Also, primary cell cultures will be used to corroboratein vitro and ex vivo effects.

Use of recreational drugs is widespread among (young) people. Although in the drug scene recreational drugs have the reputation of being safe, severe and fatal intoxications have been attributed to the use of these drugs. Also, large interindividual variations in susceptibility toward designer drugs have been observed.

Often toxicity of designer drugs appears to be caused, at least partly, by the metabolites. For a large number of drugs, cytochrome P450 (CYP) enzymes are responsible for the metabolism. Polymorphisms in CYPs may contribute to the interindividual variability in drug plasma levels and susceptibility toward designer drugs. However, bioavailability also largely depends on the expression and activity of drug transport across membranes. In particular efflux transporters of the ATP-binding cassette (ABC) family. Further, co-exposure, for example by consumption of alcohol or fruit juices or other (medicinal) drugs, can potentially interfere with designer drug metabolism and transport, leading to altered (adverse) effects.

Neuroreceptor interactions of drugs of abuse to predict human health effects (Laura Hondebrink)