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Influence of P-glycoprotein modulation on plasma concentrations and pharmacokinetics of orally administered prednisolone in dogs

Sara Van der Heyden DVM1, Siska Croubels PharmD, PhD2, Caroline Gadeyne DVM3, Richard Ducatelle DVM, PhD4, Sylvie Daminet DVM, PhD5, Hugo Murua Escobar Dipl Biol, PhD6, Katharina Sterenczak Dipl Biol, PhD7, Ingeborgh Polis DVM, PhD8, Stijn Schauvliege DVM, PhD9, Myriam Hesta DVM, PhD10, and Koen Chiers DVM, PhD11
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  • 1 Department of Pathology, Bacteriology and Poultry Diseases, Faculty of Veterinary Medicine, Ghent University, 9820 Merelbeke, Belgium.
  • | 2 Department of Pharmacology, Toxicology and Biochemistry, Faculty of Veterinary Medicine, Ghent University, 9820 Merelbeke, Belgium.
  • | 3 Department of Medicine and Clinical Biology of Small Animals, Faculty of Veterinary Medicine, Ghent University, 9820 Merelbeke, Belgium.
  • | 4 Department of Pathology, Bacteriology and Poultry Diseases, Faculty of Veterinary Medicine, Ghent University, 9820 Merelbeke, Belgium.
  • | 5 Department of Medicine and Clinical Biology of Small Animals, Faculty of Veterinary Medicine, Ghent University, 9820 Merelbeke, Belgium.
  • | 6 Small Animal Clinic, University of Veterinary Medicine, 30559, Hannover, Germany.
  • | 7 Small Animal Clinic, University of Veterinary Medicine, 30559, Hannover, Germany.
  • | 8 Department of Medicine and Clinical Biology of Small Animals, Faculty of Veterinary Medicine, Ghent University, 9820 Merelbeke, Belgium.
  • | 9 Department of Surgery and Anesthesiology of Domestic Animals, Faculty of Veterinary Medicine, Ghent University, 9820 Merelbeke, Belgium.
  • | 10 Department of Nutrition, Genetics and Ethology, Faculty of Veterinary Medicine, Ghent University, 9820 Merelbeke, Belgium.
  • | 11 Department of Pathology, Bacteriology and Poultry Diseases, Faculty of Veterinary Medicine, Ghent University, 9820 Merelbeke, Belgium.

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.

Animals—7 healthy adult Beagles.

Procedures—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 and Clinical Relevance—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.

Contributor Notes

Dr. Van der Heyden's present address is Subunit of Pathology & Prionology, Veterinary and Agrochemical Research Centre, VAR-CODA-CERVA, Groeselenberg 99, 1180 Ukkel, Belgium.

Presented in abstract form at the 28th European Society of Veterinary Pathology and European College of Veterinary Pathologists Congress, Belgrade, Serbia, September 2010.

The authors thank Christian Puttevils, Delphine Ameye, Isabel De Bleeker, Herman De Rijcke, Maggy Geerinck, An Maes, and Sarah Loomans for technical assistance.

Address correspondence to Dr. Van der Heyden (Sara.VanderHeyden@coda-cerva.be).