Abstract

Experimental studies indicate that short-term fasting alters drug metabolism. However, the effects of short-term fasting on drug metabolism in human need further investigation. Therefore, the aim of this study was to evaluate the effects of short-term fasting (36h) on CYP450-mediated drug metabolism. In a randomized cross-over study design, nine healthy subjects ingested a cocktail consisting of five CYP-specific probe-drugs (caffeine [CYP1A2], S-warfarin [CYP2C9], omeprazole [CYP2C19], metoprolol [CYP2D6] and midazolam [CYP3A4]) on two occasions (control study after an overnight fast and after 36h of fasting). Blood samples were drawn for pharmacokinetic (PK) analysis using nonlinear mixed effects modeling (NONMEM). In addition, we studied in Wistar rats the effects of short-term fasting on hepatic mRNA expression of CYP-isoforms corresponding with the five studied CYP-enzymes in humans. In the healthy subjects, short-term fasting increased oral caffeine clearance by 20% (p=0.03) and decreased oral S-warfarin clearance by 25% (p<0.001). In rats, short-term fasting increased mRNA expression of the orthologs of human CYP1A2, CYP2C19, CYP2D6, CYP3A4 (p<0.05) and decreased the mRNA expression of the ortholog of CYP2C9 (p<0.001) compared to the post-absorptive state. These results demonstrate that short-term fasting alters cytochrome P450-mediated drug metabolism in a non-uniform pattern. Therefore, short-term fasting is another factor affecting cytochrome P450-mediated drug metabolism in humans.