Avermectin transepithelial transport in MDR1- and MRP-transfected canine kidney monolayers

Abstract

Fluxes of the anti-parasitic agents, [(3)H]-ivermectin, [(3)H]-selamectin and [(3)H]-moxidectin were studied across non-transfected and transfected canine kidney epithelial monolayers, MDCK II/wt, MDCK II-MDR1, MDCK II-MRP1 and MDCK II-MRP2. All four lines surprisingly expressed significant levels of P-glycoprotein (P-gp), coded for by MDR1, but MDCK II-MDR1 expressed increased levels compared to the other lines. MDCK II-MRP1 and MDCK II-MRP2 expressed increased levels of MRP1 and MRP2 respectively. Fluxes of [(3)H]-ivermectin, [(3)H]-selamectin, [(3)H]-moxidectin, and the P-gp substrates, rhodamine-123 and DiOC(2), were polarized in the basolateral-to-apical (secretory) direction across the four lines. Selected MRP inhibitors used in relevant pharmacological concentrations did not block the secretory fluxes of either [(3)H]-ivermectin or [(3)H]-selamectin in either the non-transfected or MRP-transfected lines. In contrast, secretory fluxes of ivermectin and selamectin were inhibited in all four lines by the P-gp inhibitor, verapamil. These data confirm that ivermectin and selamectin are substrates for P-gp in four additional cell lines, but suggest that they are not significant substrates for MRP1 or MRP2 where there is background expression of P-gp. Since this pattern of expression also pertains on the blood-brain barrier, it is unlikely that MRP1 and MRP2 play a significant role in ivermectin and selamectin blood: brain distribution in vivo.

Characterization of multidrug transporter-mediated efflux of avermectins in human and mouse neuroblastoma cell lines

“…Competition for MDR1/Mdr1 function by ivermectin (K i 0.24 mM) correlates with peak plasma ivermectin concentrations found in man (0.05-0.1 mM), suggesting that kinetics in these in vitro models may be relevant to in vivo exposure levels (Ottesen and Campbell, 1994;González Canga et al, 2008). Brayden and Griffin (2008), found that there was no significant MRP-1-or MRP-2-mediated avermectin transport in the presence of functional MDR1. As with doxorubicin and vincristine, which are substrates for multiple transporters (Fung and Gottesmann, 2009), however, overlapping substrate specificity between MDR1 and MRP isoforms may provide an alternative route of efflux for these avermectins if MDR1/Mdr1 were inhibited.…”

“…These observations were extended when Lespine et al, (2007) showed that ivermectin, abamectin, doramectin, eprinomectin, and selamectin were potent inhibitors of rhodamine-123 dye efflux from porcine kidney epithelial cells transfected with either mouse Mdr1a or human MDR1. Equally, an increase in basolateral-to-apical flux of [ 3 H]-ivermectin and [ 3 H]-selamectin was found in monolayers of MDCKII-MDR1 cells compared to wildtype MDCKII; this was significantly reduced by the bilateral addition of the MDR1 inhibitor verapamil (100 mM), (Brayden and Griffin, 2008). The data presented in this paper show abamectin, emamectin and ivermectin competition for MDR1 and Mdr1a-mediated H33342 dye efflux comparable to CSA in both SH-SY5Y and N2a cell lines respectively, consistent with these avermectins being potential substrates for MDR1/Mdr1 in the CNS/blood brain barrier of both species.…”

“…There are currently conflicting data as to whether MRP isoforms play a role in avermectin disposition. In one study, it was shown that ivermectin and selamectin were substrates for MDR1 but that inhibitors of MRPs had no effect upon the flux of ivermectin and selamectin in either mock-transfected MDCKII cells or in MDCKII-MRP1 or MDCK-MRP2 transfected cells (Brayden and Griffin, 2008). Excretion of ivermectin from functionally intact porcine brain endothelial capillaries was mediated by Mdr1 but not Mrp (Nobmann et al, 2001).…”

Natural Allelic Variants of Bovine ATP-Binding Cassette Transporter ABCG2: Increased Activity of the Ser581 Variant and Development of Tools for the Discovery of New ABCG2 Inhibitors

“…It has been shown to be a good inhibitor of the human transporter (Imai et al, 2004). Ivermectin and selamectin are potent anthelmintic drugs that interact with other ABC transporters like P-glycoprotein (Griffin et al, 2005;Brayden and Griffin, 2008). In this article, both antiparasitic drugs were identified as new inhibitors of the bovine, mouse, and human ABCG2.…”

Interaction of Macrocyclic Lactones with the Multidrug Transporters: The Bases of the Pharmacokinetics of Lipid-Like Drugs

“…Selamectin is an interesting structural intermediate, with only one sugar residue. It resembles ivermectin in terms of P-gp inhibition [33] and transport [70,71] but has a lower affinity for the transporter ( Table 1). On the basis of the different ability of doramectin and selamectin, that only differ structurally by one sugar unit, to compete with verapamil on P-gp [33], the data indicate that the second sugar unit plays an important role in the interaction with Pgp.…”