Establishment of a cell line for assessing drugs as canine P‐glycoprotein substrates: proof of principle

Abstract

P-glycoprotein (P-gp), encoded by the ABCB1 (MDR1) gene, dramatically impacts drug disposition. P-gp is expressed in the intestines, biliary canaliculi, renal tubules, and brain capillaries where it functions to efflux substrate drugs. In this capacity, P-gp restricts oral absorption, enhances biliary and renal excretion, and inhibits central nervous system entry of substrate drugs. Many drugs commonly used in veterinary medicine are known substrates for canine P-gp (vincristine, loperamide, ivermectin, others). Because these drugs have a narrow therapeutic index, defective P-gp function can cause serious adverse drug reactions due to enhanced brain penetration and/or decreased clearance. P-gp dysfunction in dogs can be intrinsic (dogs harboring ABCB1-1Δ) or acquired (drug interactions between a P-gp inhibitor and P-gp substrate). New human drug candidates are required to undergo assessment for P-gp interactions according to FDA and EMA regulations to avoid adverse drug reactions and drug-drug interactions. Similar information regarding canine P-gp could prevent adverse drug reactions in dogs. Because differences in P-gp substrates have been documented between species, one should not presume that human or murine P-gp substrates are necessarily canine P-gp substrates. Thus, our goal was to develop a cell line for assessing drugs as canine P-gp substrates.

Comparing the immunogenicity of glycosidase-directed resiquimod prodrugs mediated by cancer cell metabolism

“…In order to investigate the efflux of RSQ from cancer cells, we first looked for P-gp expression in each cancer cell line by Western blot (Fig. 4c ) [ 39 ]. P-gp was detected in TC2 and B16 cells but not in 4T1 cells.…”

Drug repurposing in oncology: Compounds, pathways, phenotypes and computational approaches for colorectal cancer

“…Due to the fact that ivermectin, a substrate of P-glycoprotein (P-gp), belongs to the NTID class, defective P-gp function can cause serious adverse drug reactions due to increased brain penetration and/or decreased clearance [ 133 ]. It is therefore important to ensure that (i) benefits of treatment with a drug candidate would outperform the side effects and (ii) careful titration and PD monitoring is necessary to obtain desired clinical outcome [ 134 ].…”

Clinical and Laboratory Findings in Dogs Undergoing Adjuvant Chemotherapy with Gemcitabine/Carboplatin Combination for Mammary Neoplasia

“…Border Collie breed dogs may have polymorphisms (Alves et al, 2011) and even nt230 (del4) ABCB1 gene mutation (Dekel et al, 2017;Marelli et al, 2020), interfering with glycoprotein P substrates metabolism. Several chemotherapeutic agents have already been identified as substrates of the glycoprotein P (Mealey, 2004;Linardi and Natalini, 2006;Mealey et al, 2017), but gemcitabine and carboplatin were not so far. Thus, no PCR test for ABCB1 mutation was requested for the Border Collie dog that showed exacerbated toxicity compared to other animals studied.…”