Biliary excretion of technetium-99m-sestamibi in wild-type dogs and in dogs with intrinsic (ABCB1-1Δ mutation) and extrinsic (ketoconazole treated) P-glycoprotein deficiency

• Published in: Journal of veterinary pharmacology and therapeutics Vol. 32; no. 5; pp. 417 - 421
• Main Authors: COELHO, J. C., TUCKER, R., MATTOON, J., ROBERTS, G., WAITING, D. K., MEALEY, K. L.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-10-2009
• Subjects: Animals; ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors; ATP-Binding Cassette, Sub-Family B, Member 1 - deficiency; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; Bile; Dogs - genetics; Dogs - metabolism; Drug Interactions; Female; Gallbladder - drug effects; Gallbladder - physiology; Gamma Cameras; Ketoconazole - pharmacology; Male; Polymorphism, Genetic; Technetium Tc 99m Sestamibi - pharmacokinetics
• ISSN: 0140-7783; 1365-2885
• DOI: 10.1111/j.1365-2885.2009.01068.x

P‐glycoprotein (P‐gp), the product of ABCB1 gene, is thought to play a role in the biliary excretion of a variety of drugs, but specific studies in dogs have not been performed. Because a number of endogenous (ABCB1 polymorphisms) and exogenous (pharmacological P‐gp inhibition) factors can interfere with normal P‐gp function, a better understanding of P‐gp’s role in biliary drug excretion is crucial in preventing adverse drug reactions and drug–drug interactions in dogs. The objectives of this study were to compare biliary excretion of technetium‐99m‐sestamibi (99mTc‐MIBI), a radio‐labelled P‐gp substrate, in wild‐type dogs (ABCB1 wild/wild), and dogs with intrinsic and extrinsic deficiencies in P‐gp function. Dogs with intrinsic P‐gp deficiency included ABCB1 mut/mut dogs, and dogs with presumed intermediate P‐gp phenotype (ABCB1 mut/wild). Dogs with extrinsic P‐gp deficiency were considered to be ABCB1 wild/wild dogs treated with the P‐gp inhibitor ketoconazole (5 mg/kg PO q12h × 9 doses). Results from this study indicate that ABCB1 mut/mut dogs have significantly decreased biliary excretion of 99mTc‐MIBI compared with ABCB1 wild/wild dogs. Treatment with ketoconazole significantly decreased biliary excretion of 99mTc‐MIBI in ABCB1 wild/wild dogs. P‐gp appears to play an important role in the biliary excretion of 99mTc‐MIBI in dogs. It is likely that concurrent administration of a P‐gp inhibitor such as ketoconazole will decrease P‐gp‐mediated biliary excretion of other substrate drugs as well.