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

Abstract

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 ((99m)Tc-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 x 9 doses). Results from this study indicate that ABCB1 mut/mut dogs have significantly decreased biliary excretion of (99m)Tc-MIBI compared with ABCB1 wild/wild dogs. Treatment with ketoconazole significantly decreased biliary excretion of (99m)Tc-MIBI in ABCB1 wild/wild dogs. P-gp appears to play an important role in the biliary excretion of (99m)Tc-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.

Toxicology of Avermectins and Milbemycins (Macrocylic Lactones) and the Role of P-Glycoprotein in Dogs and Cats

“…Ivermectin plasma levels did not differ between normal and ivermectin-sensitive collies administered 0.1 mg/kg ivermectin orally, 52 but 0.1 mg/kg may be too small a dose for pharmacokinetic differences to be evident. It has been demonstrated that dogs with the ABCB1 defect are impaired in the ability to eliminate P-gp substrates into the bile 53 but do not appear to have enhanced intestinal absorption of P-gp substrates. 54 However, MLs were not evaluated in the latter two studies.…”

“…An additional consideration is that dogs with the ABCB1-1 Δ gene defect may have minimal biliary elimination of P-gp substrates due to nonfunctional P-gp. 53 Therefore, repeated doses of activated charcoal may not be of much benefit in these animals, although this has not been proven. Because the amounts of MLs eliminated in bile in canines have not been evaluated, this would be an excellent avenue for further research that would help better answer questions about the role of repeated administration of activated charcoal in both wild-type and P-gp– defective dogs.…”

Adverse Drug Reactions in Veterinary Patients Associated with Drug Transporters

“…Ketoconazole inhibits biliary excretion of 99m Tc-sestamibi in MDR1(normal/normal) dogs. 17 For P-gp substrate drugs with a narrow therapeutic index (ie, vincristine, doxorubicin), concurrent administration of a drug that inhibits P-gp function should be avoided. Drugs known to inhibit P-gp function in dogs include ketoconazole, cyclosporine, and spinosad.…”

Ivermectin

“…23 There it functions as an efflux pump for a large number of substrate drugs (Box 52-1), binding the drug and transporting it back into the capillary lumen. 27 Similarly, concurrent administration of the flea preventive spinosad (Comfortis) and ivermectin (extralabel dose used for treating demodex) has been reported by the FDA to cause neurologic toxicity (http://www.fda.gov/AnimalVeterinary/NewsEvents/CVMUpdat es/ucm047942.htm). In addition to increased sensitivity to macrolide antiparasitic agents, collies and other herding breeds harboring the MDR1 mutant genotype have severe neurotoxicity develop after treatment with standard doses of loperamide (Imodium), 24 and are extremely sensitive to adverse effects caused by standard doses of vincristine and doxorubicin.…”