Nutritional conditioning The effect of a short-term high fat diet on hepatic drug metabolism

This thesis presents proof of concept studies on the effects of a short-term hypercaloric high fat diet on hepatic drug metabolism in healthy subjects. Knowledge of factors contributing to inter- and intraindividual variability in drug exposure is important to prevent treatment failure or untoward side effects. A three-day hypercaloric high fat diet - consisting of a regular diet supplemented with 500 mL of cream - induces steatotic liver alterations in humans. These accumulating lipids may act as ligands that activate nuclear receptors, thereby potentially modulating gene expression of hepatic drug metabolizing enzymes.
A validated cocktail containing five cytochrome P450 specific probe drugs was administered to healthy subjects to phenotype drug metabolizing enzyme activity after a regular diet and after a three-day hypercaloric high fat diet. Furthermore, midazolam and acetaminophen were used as probes to study the effects on other metabolic pathways such as uridine diphosphate-glucuronosyltransferases (UGT).
The results of the studies demonstrate a potential interaction between a high fat diet and hepatic drug metabolism; particularly drugs metabolized by CYP2C19 (possibly CYP3A4) and CYP2E1 might be affected. Importantly, a high fat diet may contribute to the risk of acetaminophen-induced liver injury because it increases exposure to acetaminophen metabolites that are related to hepatotoxicity. The average effects appear to be small, but still may be important for drugs with a narrow therapeutic window or in combination with other factors that alter drug disposition.