Loperamide‐induced expression of immune and inflammatory genes in Collies associated with ivermectin sensitivity

Abstract

This study evaluated the impact of the ABCB1-1Δ mutation in Collies which exhibited toxicity toward ivermectin, on changes in gene expression when given the unrelated ABCB1 substrate loperamide, to identify potential biomarkers predictive of drug safety. Thirty-two healthy intact Collies consisting of dogs with either a wild-type, heterozygous mutant, or homozygous mutant genotype were used. Whole blood samples were collected from Collies at 0 or 5 h following administration of loperamide at a dose of 0.10 mg/kg. Whole-genome gene expression microarray was conducted to examine for changes in gene expression. Microarray analysis identified loperamide-induced changes in gene expression which were specifically associated with ivermectin-sensitive phenotypes in Collies possessing the ABCB1-1Δ mutation. Gene pathway analysis further demonstrated that the altered genes are involved in immunological disease, cell death and survival, and cellular development. Thirteen genes, including CCL8 and IL-8, were identified. Collie dogs harboring ABCB1-1Δ mutation which also exhibited toxicity toward ivermectin demonstrated systematic responses following loperamide treatment exhibited by altered expression of genes involved in immune and inflammatory signaling pathways. Genes such as CCL8 and IL-8 are potential biomarkers in whole blood that may predict the safety of loperamide in dogs with ABCB1-1∆ mutation associated with ivermectin sensitivity.

Canine and feline P‐glycoprotein deficiency: What we know and where we need to go

“…Thus, neurological manifestations of P‐gp substrate drugs in P‐gp deficient animals appear to be primarily a function of enhanced penetration across the blood brain barrier rather than greater systemic exposure. These neurological effects were seen in all MDR1 mutant/mutant dogs treated with loperamide at the 0.2 mg/kg dose and in the majority of MDR1 mutant/mutant dogs treated at the 0.1 mg/kg dose (Mealey & Burke, 2015 ; Mealey, Greene, et al, 2008 ; Zhu et al, 2016 ). As might be expected, dogs with an intermediate P‐gp phenotype (MDR1 mutant/normal), loperamide‐induced neurological clinical signs are milder than in dogs with a P‐gp null phenotype (MDR1 mutant/mutant).…”

“…Another group (Kitamura et al, 2008) that investigated the pharmacokinetics of orally administered fexofenadine, quinidine, and loperamide in P-gp deficient in wildtype collies identified no statistical differences in Cmax or AUC of any of those P-gp substrates. The group identified a significant difference in plasma fexofenadine concentrations at two of 6 time points Note: Barbet et al, 2009;Campbell et al, 2017;Deshpande et al, 2016;Gaens et al, 2019;Griffin et al, 2005;Heit et al, 2021;Mackin et al, 2020;Mealey et al, 2001;Mealey et al, 2017;Mealey, Fidel, et al, 2008;Mealey, Greene, et al, 2008;Meyers et al, 2015;Swain et al, 2013;West & Mealey, 2007;Zhu et al, 2016. a Anecdotal information also exists for vinblastine and vinorelbine.…”

“… Note : Barbet et al, 2009 ; Campbell et al, 2017 ; Deshpande et al, 2016 ; Gaens et al, 2019 ; Griffin et al, 2005; Heit et al, 2021 ; Mackin et al, 2020 ; Mealey et al, 2001 ; Mealey et al, 2017 ; Mealey, Fidel, et al, 2008 ; Mealey, Greene, et al, 2008 ; Meyers et al, 2015 ; Swain et al, 2013 ; West & Mealey, 2007 ; Zhu et al, 2016 . a Anecdotal information also exists for vinblastine and vinorelbine.…”