TY - JOUR T1 - Short-Term Fasting alters Cytochrome P450 mediated Drug Metabolism in Humans JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.114.062299 SP - dmd.114.062299 AU - Laureen Alice Lammers AU - Roos Achterbergh AU - Emmely M. de Vries AU - F. Samuel van Nierop AU - Heinz-Josef Klumpen AU - Maarten R. Soeters AU - Anita Boelen AU - Johannes A. Romijn AU - Ron A.A. Mathot Y1 - 2015/03/20 UR - http://dmd.aspetjournals.org/content/early/2015/03/20/dmd.114.062299.abstract N2 - 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. ER -