title: Influence of P-glycoprotein modulation on plasma concentrations and pharmacokinetics of orally administered prednisolone in dogs.
abstract: OBJECTIVE
  To evaluate the impact of modulation of the membrane-bound efflux pump P-glycoprotein (P-gp) on plasma concentrations of orally administered prednisolone in dogs.
  
  
  METHODS
  7 healthy adult Beagles.
  
  
  METHODS
  Each dog received 3 treatments (control [no treatment], rifampicin [100 mg/d, PO, for 21 days, as an inducer of P-gp], and ketoconazole [100 mg/d, PO, for 21 days, as an inhibitor of P-gp]). A single dose of prednisolone (1 mg/kg, PO) was administered on day 8 of each treatment period. There was a 7-day washout period between subsequent treatments. Plasma concentrations of prednisolone were determined by use of a validated liquid chromatography-tandem mass spectrometry method. Duodenum and colon biopsy specimens were obtained endoscopically from anesthetized dogs and assessed for P-gp protein labeling via immunohistochemical analysis and mRNA quantification via real-time PCR assay. Total fecal collection was performed for evaluation of effects of P-gp modulation on digestion of nutrients.
  
  
  RESULTS
  Rifampicin treatment upregulated duodenal P-gp in dogs and significantly reduced the area under the plasma concentration-time curve of prednisolone. Ketoconazole typically downregulated expression of duodenal P-gp, with a subsequent increase in the area under the plasma concentration-time curve of prednisolone. There was a noticeable interindividual difference in response. Digestion of nutrients was not affected.
  
  
  CONCLUSIONS
  Modulation of P-gp expression influenced plasma concentrations of prednisolone after oral administration in dogs. Thus, treatment response to prednisolone may be influenced by coadministration of P-gp-modulating medications or feed ingredients.
authors.affiliation: Department of Pathology, Bacteriology and Poultry Diseases, Faculty of Veterinary Medicine, Ghent University, 9820 Merelbeke, Belgium. Sara.VanderHeyden@coda-cerva.be
authors.forename: Sara
authors.initials: S
authors.lastname: Van der Heyden
authors.forename: Siska
authors.initials: S
authors.lastname: Croubels
authors.forename: Caroline
authors.initials: C
authors.lastname: Gadeyne
authors.forename: Richard
authors.initials: R
authors.lastname: Ducatelle
authors.forename: Sylvie
authors.initials: S
authors.lastname: Daminet
authors.forename: Hugo
authors.initials: H
authors.lastname: Murua Escobar
authors.forename: Katharina
authors.initials: K
authors.lastname: Sterenczak
authors.forename: Ingeborgh
authors.initials: I
authors.lastname: Polis
authors.forename: Stijn
authors.initials: S
authors.lastname: Schauvliege
authors.forename: Myriam
authors.initials: M
authors.lastname: Hesta
authors.forename: Koen
authors.initials: K
authors.lastname: Chiers
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D019540:Area Under Curve; D001706:Biopsy / Q000662:veterinary; D002853:Chromatography, Liquid / Q000662:veterinary; D004285:Dogs; D005786:Gene Expression Regulation / Q000187:drug effects*; D007654:Ketoconazole / Q000008:administration & dosage / Q000494:pharmacology*; D011239:Prednisolone / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D060888:Real-Time Polymerase Chain Reaction / Q000662:veterinary; D012293:Rifampin / Q000008:administration & dosage / Q000494:pharmacology*; D053719:Tandem Mass Spectrometry / Q000662:veterinary
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011239:Prednisolone; D007654:Ketoconazole; D012293:Rifampin