title: Effect of Short-Term Fasting on Systemic Cytochrome P450-Mediated Drug Metabolism in Healthy Subjects: A Randomized, Controlled, Crossover Study Using a Cocktail Approach.
abstract: Short-term fasting can alter drug exposure but it is unknown whether this is an effect of altered oral bioavailability and/or systemic clearance. Therefore, the aim of our study was to assess the effect of short-term fasting on oral bioavailability and systemic clearance of different drugs.
  
  
  
  In a randomized, controlled, crossover trial, 12 healthy subjects received a single administration of a cytochrome P450 (CYP) probe cocktail, consisting of caffeine (CYP1A2), metoprolol (CYP2D6), midazolam (CYP3A4), omeprazole (CYP2C19) and warfarin (CYP2C9), on four occasions: an oral (1) and intravenous (2) administration after an overnight fast (control) and an oral (3) and intravenous (4) administration after 36 h of fasting. Pharmacokinetic parameters of the probe drugs were analyzed using the nonlinear mixed-effects modeling software NONMEM.
  
  
  
  Short-term fasting increased systemic caffeine clearance by 17% (p = 0.04) and metoprolol clearance by 13% (p < 0.01), whereas S-warfarin clearance decreased by 19% (p < 0.01). Fasting did not affect bioavailability.
  
  
  
  The study demonstrates that short-term fasting alters CYP-mediated drug metabolism in a non-uniform pattern without affecting oral bioavailability.
authors.affiliation: Department of Hospital Pharmacy, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. l.a.tenberg-lammers@amc.uva.nl.
authors.forename: Laureen A
authors.initials: LA
authors.lastname: Lammers
authors.affiliation: Department of Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Roos
authors.initials: R
authors.lastname: Achterbergh
authors.affiliation: Department of Clinical Chemistry, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Ron H N
authors.initials: RHN
authors.lastname: van Schaik
authors.affiliation: Department of Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Romijn
authors.affiliation: Department of Hospital Pharmacy, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
authors.forename: Ron A A
authors.initials: RAA
authors.lastname: Mathôt
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000328:Adult; D002110:Caffeine / Q000008:administration & dosage / Q000378:metabolism; D018592:Cross-Over Studies; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D065729:Cytochrome P-450 CYP2C9 / Q000378:metabolism*; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004338:Drug Combinations; D005215:Fasting / Q000378:metabolism*; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008790:Metoprolol / Q000008:administration & dosage / Q000378:metabolism; D008874:Midazolam / Q000008:administration & dosage / Q000378:metabolism; D009853:Omeprazole / Q000008:administration & dosage / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000378:metabolism*; D013997:Time Factors; D014859:Warfarin / Q000008:administration & dosage / Q000378:metabolism; D055815:Young Adult
chemical_list: D004338:Drug Combinations; D004364:Pharmaceutical Preparations; D002110:Caffeine; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2; D019389:Cytochrome P-450 CYP2D6; D008790:Metoprolol; D009853:Omeprazole; D008874:Midazolam
keywords: Caffeine; Mean Transit Time; Metoprolol; Omeprazole; Systemic Clearance