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

作者：Brayden David J^*; Griffin Joanna

来源：Veterinary Research Communications, 2008, 32(1): 93-106.

DOI：10.1007/s11259-007-9007-9

• blood-brain barrier
• ivermectin
• multidrug-resistance associated proteins
• P-glycoprotein efflux
• selamectin

Fluxes of the anti-parasitic agents, [H-3]-ivermectin, [H-3]-selamectin and [H-3]-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 [H-3]-ivermectin, [H-3]-selamectin, [H-3]-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 [H-3]-ivermectin or [H-3]-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.

• 出版日期2008-1