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Influence of P-glycoprotein modulation on plasma concentrations and pharmacokinetics of orally administered prednisolone in dogs.
- Source :
-
American journal of veterinary research [Am J Vet Res] 2012 Jun; Vol. 73 (6), pp. 900-7. - Publication Year :
- 2012
-
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.<br />Animals: 7 healthy adult Beagles.<br />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.<br />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.<br />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.
- Subjects :
- Administration, Oral
Analysis of Variance
Animals
Area Under Curve
Biopsy veterinary
Chromatography, Liquid veterinary
Dogs
Ketoconazole administration & dosage
Prednisolone administration & dosage
Prednisolone blood
Real-Time Polymerase Chain Reaction veterinary
Rifampin administration & dosage
Tandem Mass Spectrometry veterinary
ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism
Gene Expression Regulation drug effects
Ketoconazole pharmacology
Prednisolone metabolism
Prednisolone pharmacokinetics
Rifampin pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1943-5681
- Volume :
- 73
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- American journal of veterinary research
- Publication Type :
- Academic Journal
- Accession number :
- 22620706
- Full Text :
- https://doi.org/10.2460/ajvr.73.6.900