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

Heyden, Sara van der, Croubels, Siska, Gadeyne, Caroline, Ducatelle, Richard, Daminet, Sylvie, Escobar, Hugo Murua, Sterenczak, Katharina, Polis, Ingeborgh, Schauvliege, Stijn, Hesta, Myriam, Chiers, Koen
American journal of veterinary research 2012 v.73 no.6 pp. 900-907
Beagle, adults, biopsy, colon, digestion, dogs, duodenum, immunohistochemistry, ingredients, ketoconazole, liquid chromatography, messenger RNA, nutrients, oral administration, pharmacokinetics, prednisolone, quantitative polymerase chain reaction, rifampicin, tandem mass spectrometry, transporters
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.