title: Fasting-Induced Changes in Hepatic P450 Mediated Drug Metabolism Are Largely Independent of the Constitutive Androstane Receptor CAR.
abstract: BACKGROUND
  Hepatic drug metabolism by cytochrome P450 enzymes is altered by the nutritional status of patients. The expression of P450 enzymes is partly regulated by the constitutive androstane receptor (CAR). Fasting regulates the expression of both P450 enzymes and CAR and affects hepatic drug clearance. We hypothesized that the fasting-induced alterations in P450 mediated drug clearance are mediated by CAR.
  
  
  METHODS
  To investigate this we used a drug cocktail validated in humans consisting of five widely prescribed drugs as probes for specific P450 enzymes: caffeine (CYP1A2), metoprolol (CYP2D6), omeprazole (CYP2C19), midazolam (CYP3A4) and s-warfarin (CYP2C9). This cocktail was administered to wild type (WT, C57Bl/6) mice or mice deficient for CAR (CAR-/-) that were either fed ad libitum or fasted for 24 hours. Blood was sampled at predefined intervals and drug concentrations were measured as well as hepatic mRNA expression of homologous/orthologous P450 enzymes (Cyp1a2, Cyp2d22, Cyp3a11, Cyp2c37, Cyp2c38 and Cyp2c65).
  
  
  RESULTS
  Fasting decreased Cyp1a2 and Cyp2d22 expression and increased Cyp3a11 and Cyp2c38 expression in both WT and CAR-/- mice. The decrease in Cyp1a2 was diminished in CAR-/- in comparison with WT mice. Basal Cyp2c37 expression was lower in CAR-/- compared to WT mice. Fasting decreased the clearance of all drugs tested in both WT and CAR-/- mice. The absence of CAR was associated with an decrease in the clearance of omeprazole, metoprolol and midazolam in fed mice. The fasting-induced reduction in clearance of s-warfarin was greater in WT than in CAR-/-. The changes in drug clearance correlated with the expression pattern of the specific P450 enzymes in case of Cyp1a2-caffeine and Cyp2c37-omeprazole.
  
  
  CONCLUSIONS
  We conclude that CAR is important for hepatic clearance of several widely prescribed drugs metabolized by P450 enzymes. However the fasting-induced alterations in P450 mediated drug clearance are largely independent of CAR.
authors.affiliation: Department of Medicine, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands.
authors.forename: E M
authors.initials: EM
authors.lastname: de Vries
authors.affiliation: Department of Hospital Pharmacy, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands.
authors.forename: L A
authors.initials: LA
authors.lastname: Lammers
authors.affiliation: Department of Medical Oncology, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Achterbergh
authors.affiliation: Department of Medical Oncology, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Klümpen
authors.affiliation: Department of Hospital Pharmacy, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands.
authors.forename: R A A
authors.initials: RA
authors.lastname: Mathot
authors.affiliation: Department of Endocrinology and Metabolism, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Boelen
authors.affiliation: Department of Medicine, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands.
authors.forename: J A
authors.initials: JA
authors.lastname: Romijn
mesh_terms: D000818:Animals; D002110:Caffeine / Q000097:blood / Q000494:pharmacology; D000090702:Constitutive Androstane Receptor; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D000072467:Cytochrome P450 Family 2 / Q000235:genetics / Q000378:metabolism; D005215:Fasting; D005260:Female; D005786:Gene Expression Regulation; D008658:Inactivation, Metabolic / Q000235:genetics*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008790:Metoprolol / Q000097:blood / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008874:Midazolam / Q000097:blood / Q000494:pharmacology; D009853:Omeprazole / Q000097:blood / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency* / Q000235:genetics; D014859:Warfarin / Q000097:blood / Q000494:pharmacology
chemical_list: D000090702:Constitutive Androstane Receptor; D008565:Membrane Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D002110:Caffeine; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; C000610388:cytochrome P-450 2C37, mouse; C542274:CYP2C38 protein, mouse; C414739:Cyp2d22 protein, mouse; C496508:Cyp3a11 protein, mouse; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; C000617645:cytochrome P-450 1A2, mouse; D008790:Metoprolol; D009853:Omeprazole; D008874:Midazolam