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

被引:40
作者
Brayden, David J. [1 ]
Griffin, Joanna [1 ]
机构
[1] Univ Coll Dublin, Sch Agr Food Sci & Vet Med, Dublin, Ireland
关键词
blood-brain barrier; ivermectin; multidrug-resistance associated proteins; P-glycoprotein efflux; selamectin;
D O I
10.1007/s11259-007-9007-9
中图分类号
S85 [动物医学(兽医学)];
学科分类号
0906 ;
摘要
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.
引用
收藏
页码:93 / 106
页数:14
相关论文
共 63 条
[1]  
Alvarez Ana I., 2006, Current Drug Delivery, V3, P199, DOI 10.2174/156720106776359195
[2]   Functional multidrug resistance protein (MRP1) lacking the N-terminal transmembrane domain [J].
Bakos, E ;
Evers, R ;
Szakács, G ;
Tusnády, GE ;
Welker, E ;
Szabó, K ;
de Haas, M ;
van Deemter, L ;
Borst, P ;
Váradi, A ;
Sarkadi, B .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (48) :32167-32175
[3]   Selamectin: a novel broad-spectrum endectocide for dogs and cats [J].
Bishop, BF ;
Bruce, CI ;
Evans, NA ;
Goudie, AC ;
Gration, KAE ;
Gibson, SP ;
Pacey, MS ;
Perry, DA ;
Walshe, NDA ;
Witty, MJ .
VETERINARY PARASITOLOGY, 2000, 91 (3-4) :163-176
[4]   Chloride channels as tools for developing selective insecticides [J].
Bloomquist, JR .
ARCHIVES OF INSECT BIOCHEMISTRY AND PHYSIOLOGY, 2003, 54 (04) :145-156
[5]   The multidrug resistance protein family [J].
Borst, P ;
Evers, R ;
Kool, M ;
Wijnholds, J .
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, 1999, 1461 (02) :347-357
[6]   IVERMECTIN - A REVIEW OF EFFICACY AND SAFETY [J].
CAMPBELL, WC ;
BENZ, GW .
JOURNAL OF VETERINARY PHARMACOLOGY AND THERAPEUTICS, 1984, 7 (01) :1-16
[7]  
CHAUDHARY PM, 1992, BLOOD, V80, P2735
[8]   Transport of glutathione and glutathione conjugates by MRP1 [J].
Cole, Susan P. C. ;
Deeley, Roger G. .
TRENDS IN PHARMACOLOGICAL SCIENCES, 2006, 27 (08) :438-446
[9]   Sequencing and tissue distribution of the canine MRP2 gene compared with MRP1 and MDR1 [J].
Conrad, S ;
Viertelhaus, A ;
Orzechowski, A ;
Hoogstraate, J ;
Gjellan, K ;
Schrenk, D ;
Kauffmann, HM .
TOXICOLOGY, 2001, 156 (2-3) :81-91
[10]   MULTIDRUG-RESISTANCE GENE (P-GLYCOPROTEIN) IS EXPRESSED BY ENDOTHELIAL-CELLS AT BLOOD-BRAIN BARRIER SITES [J].
CORDONCARDO, C ;
OBRIEN, JP ;
CASALS, D ;
RITTMANGRAUER, L ;
BIEDLER, JL ;
MELAMED, MR ;
BERTINO, JR .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1989, 86 (02) :695-698