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

Author:
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
Source:
American journal of veterinary research 2012 v.73 no.6 pp. 900-907
ISSN:
0002-9645
Subject:
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
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.
Agid:
319199