Nutritional conditioning: The effect of fasting on drug metabolism

The studies described in this thesis focus on the effect of fasting, as nutritional modulator, on drug metabolism. Drug metabolism varies considerably between and within patients, which may result in treatment failure or, conversely, in untoward side effects. Many factors contribute to the variability in drug metabolism such as (patho)physiological characteristics, genetic makeup and environmental factors. The nutritional status of a patient, such as fasting, contributes as well. This thesis presents proof of concept studies in animals and healthy subjects on the effects of short-term (36 hour) fasting on drug metabolism. Since Cytochrome P450 (CYP) enzymes play an important role in drug metabolism, a cocktail containing five CYP-specific probe drugs was administered to healthy subjects to study the effect of fasting on drug metabolizing enzymes. Furthermore, midazolam and acetaminophen were used as probes to study the effect of fasting on other metabolic pathways such as uridine diphosphate-glucuronosyltransferases (UGT), sulfotransferases (SULT) and glutathione-S-transferases (GST). The results of the studies demonstrate that short-term fasting contributes to variability in drug exposure by differentially affecting enzymes involved in human drug metabolism. Importantly, fasting increases potential liver toxicity of acetaminophen. Although the effects of fasting appear to be small (∼ 10-20%) and variability in drug metabolism cannot completely be attributed to the effects of fasting alone, short-term fasting may be relevant for drugs with a small therapeutic range and/or in combination with other factors that contribute to variability in drug metabolism