Dissertation
EXPLORING FACTORS AFFECTING PLASMA PROTEIN BINDING OF DRUGS IN DOGS: UREMIC TOXINS AND POLYMORPHISMS OF ALBUMIN AND ALPHA-1 ACID GLYCOPROTEIN
Doctor of Philosophy (PhD), Washington State University
01/2019
Handle:
https://hdl.handle.net/2376/117006
Abstract
Canine plasma protein binding is a key component in research and drug development programs to predict the efficacy and safety of new drugs. While factors influencing human plasma protein binding have been extensively studied, similar information on canine plasma protein binding is limited. The aims of this project were to evaluate the extent of drug protein binding in reference (wildtype/non-azotemic) canine plasma compared to plasma from dogs with the following traits: 1) the most common albumin polymorphisms (c.1075G>T and c.1422A>T), 2) the most common alpha-1 acid glycoprotein (or orosomucoid, ORM) polymorphism c.70G>A, or 3) increasing concentrations of select protein-bound uremic toxins (PBUTs). Equilibrium dialysis, ultracentrifugation and ultrafiltration were used to determine the extent of plasma protein binding of 5 drugs preferentially bound to albumin (D01-4582, meloxicam, celecoxib, furosemide and mycophenolic acid) and 4 drugs preferentially bound to orosomucoid (amitriptyline, indinavir, verapamil and lidocaine). For meloxicam, H1 allele plasma (reference) had statistically significant higher free drug fractions (P=0.041) than H2 allele plasma (c.1075G>T and c.1422A>T) (n=6 per group). For D01-4582, celecoxib and mycophenolic acid, there was no difference in the extent of plasma protein binding between albumin genotype groups (P>0.05, Mann-Whitney U). Similarly, orosomucoid genotype seemed to have negligible effect on free drug fractions of amitriptyline, indinavir, verapamil and lidocaine (P>0.05, Mann-Whitney U). Creatinine, urea, kynurenic acid, hippuric acid, indole-3-acetic acid sodium salt, indoxyl sulfate potassium salt and CMPF (3-carboxy-4-methyl-5-propyl-2-furanpropionic acid) were selected to evaluate the effect of PBUTs on binding of meloxicam, mycophenolic acid and furosemide in canine albumin and pooled plasma. Human serum albumin was used as control. High concentrations of PBUTs in canine plasma were associated with increased free drug fractions of meloxicam and furosemide compared to controls (P<0.05, Kruskal-Wallis). While statistical significance was only reached with supra-physiological concentrations of PBUTs, the fold-change in free drug fractions appreciated at lower concentrations may be clinically relevant in some patients with renal dysfunction. Interestingly, the decrease in albumin binding caused by PBUTs seems to be more pronounced in humans than in dogs, which should be taken into consideration when interpreting and translating pharmacokinetic data between the two species.
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Details
- Title
- EXPLORING FACTORS AFFECTING PLASMA PROTEIN BINDING OF DRUGS IN DOGS: UREMIC TOXINS AND POLYMORPHISMS OF ALBUMIN AND ALPHA-1 ACID GLYCOPROTEIN
- Creators
- Ana Petra Trindade Costa
- Contributors
- Katrina L Mealey (Advisor)Nicolas F Villarino (Committee Member)Michael H Court (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- College of Veterinary Medicine
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Number of pages
- 123
- Identifiers
- 99900581615901842
- Language
- English
- Resource Type
- Dissertation