title: Short-term fasting alters cytochrome P450-mediated drug metabolism in humans.
abstract: Experimental studies indicate that short-term fasting alters drug metabolism. However, the effects of short-term fasting on drug metabolism in humans need further investigation. Therefore, the aim of this study was to evaluate the effects of short-term fasting (36 h) on P450-mediated drug metabolism. In a randomized crossover study design, nine healthy subjects ingested a cocktail consisting of five P450-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 36 h of fasting). Blood samples were drawn for pharmacokinetic analysis using nonlinear mixed effects modeling. In addition, we studied in Wistar rats the effects of short-term fasting on hepatic mRNA expression of P450 isoforms corresponding with the five studied P450 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, and CYP3A4 (P < 0.05), and decreased the mRNA expression of the ortholog of CYP2C9 (P < 0.001) compared with the postabsorptive state. These results demonstrate that short-term fasting alters cytochrome P450-mediated drug metabolism in a nonuniform pattern. Therefore, short-term fasting is another factor affecting cytochrome P450-mediated drug metabolism in humans.
authors: Departments of Hospital Pharmacy (L.A.L., R.A.A.M.), Medicine (R.A., J.A.R.), Endocrinology and Metabolism (E.M.d.V., F.S.v.N., M.R.S., A.B.), and Medical Oncology (H.-J.K.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands l.a.tenberg-lammers@amc.uva.nl.
authors: Laureen A
authors: LA
authors: Lammers
authors: Departments of Hospital Pharmacy (L.A.L., R.A.A.M.), Medicine (R.A., J.A.R.), Endocrinology and Metabolism (E.M.d.V., F.S.v.N., M.R.S., A.B.), and Medical Oncology (H.-J.K.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Roos
authors: R
authors: Achterbergh
authors: Departments of Hospital Pharmacy (L.A.L., R.A.A.M.), Medicine (R.A., J.A.R.), Endocrinology and Metabolism (E.M.d.V., F.S.v.N., M.R.S., A.B.), and Medical Oncology (H.-J.K.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Emmely M
authors: EM
authors: de Vries
authors: Departments of Hospital Pharmacy (L.A.L., R.A.A.M.), Medicine (R.A., J.A.R.), Endocrinology and Metabolism (E.M.d.V., F.S.v.N., M.R.S., A.B.), and Medical Oncology (H.-J.K.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: F Samuel
authors: FS
authors: van Nierop
authors: Departments of Hospital Pharmacy (L.A.L., R.A.A.M.), Medicine (R.A., J.A.R.), Endocrinology and Metabolism (E.M.d.V., F.S.v.N., M.R.S., A.B.), and Medical Oncology (H.-J.K.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Heinz-Josef
authors: HJ
authors: Klümpen
authors: Departments of Hospital Pharmacy (L.A.L., R.A.A.M.), Medicine (R.A., J.A.R.), Endocrinology and Metabolism (E.M.d.V., F.S.v.N., M.R.S., A.B.), and Medical Oncology (H.-J.K.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Maarten R
authors: MR
authors: Soeters
authors: Departments of Hospital Pharmacy (L.A.L., R.A.A.M.), Medicine (R.A., J.A.R.), Endocrinology and Metabolism (E.M.d.V., F.S.v.N., M.R.S., A.B.), and Medical Oncology (H.-J.K.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Anita
authors: A
authors: Boelen
authors: Departments of Hospital Pharmacy (L.A.L., R.A.A.M.), Medicine (R.A., J.A.R.), Endocrinology and Metabolism (E.M.d.V., F.S.v.N., M.R.S., A.B.), and Medical Oncology (H.-J.K.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Johannes A
authors: JA
authors: Romijn
authors: Departments of Hospital Pharmacy (L.A.L., R.A.A.M.), Medicine (R.A., J.A.R.), Endocrinology and Metabolism (E.M.d.V., F.S.v.N., M.R.S., A.B.), and Medical Oncology (H.-J.K.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Ron A A
authors: RA
authors: Mathôt
mesh_terms: D000328:Adult; D000818:Animals; D002110:Caffeine / Q000097:blood / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism*; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics / Q000378:metabolism*; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics / Q000378:metabolism*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D005215:Fasting / Q000097:blood / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D008790:Metoprolol / Q000097:blood / Q000493:pharmacokinetics; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics; D009853:Omeprazole / Q000097:blood / Q000493:pharmacokinetics; D017208:Rats, Wistar; D014859:Warfarin / Q000097:blood / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D002110:Caffeine; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008790:Metoprolol; D009853:Omeprazole; D008874:Midazolam