Interaction of digoxin with antihypertensive drugs via MDR1.
The multidrug transporter MDR1 (P-glycoprotein)-mediated interaction between digoxin and 29 antihypertensive drugs of various types was examined by using the MDR1 overexpressing LLC-GA5-COL150 cells, which were established by transfecting MDR1 cDNA into porcine kidney epithelial LLC-PK1 cells. These cells construct monolayers with tight junctions, and enable the evaluation of transcellular transport. The MDR1 was highly expressed on the apical membrane (urine side). The basal-to-apical and apical-to-basal transcellular transport of [3H]digoxin in LLC-GA5-COL150 cells was time- and temperature-dependent. The basal-to-apical transport of [3H]digoxin was markedly increased, whereas the apical-to-basal transport was decreased in LLC-GA5-COL150 cells, compared with the host LLC-PK1 cells, suggesting that [3H]digoxin was a substrate for MDR1. Most of the Ca2+ channel blockers used here markedly inhibited basal-to-apical transport and increased apical-to-basal transport. Exceptions were diltiazem, nifedipine and nitrendipine, which hardly showed inhibitory effects on transcellular transport of [3H]digoxin. Alpha-blocker doxazosin and beta-blocker carvedilol also inhibited transcellular transport of [3H]digoxin, but none of the angiotensin converting enzyme inhibitors and AT1 angiotensin II receptor antagonists used here were active. These observations will promote understanding of the digoxin-drug interactions resulting from their actions on MDR1, and which may aid in avoiding these unexpected effects of digoxin.
Takara
Kohji
K
Department of Hospital Pharmacy, School of Medicine, Kobe University, Japan.
Kakumoto
Mikio
M
Tanigawara
Yusuke
Y
Funakoshi
Junko
J
Sakaeda
Toshiyuki
T
Okumura
Katsuhiko
K
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D000959:Antihypertensive Agents / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D004077:Digoxin / Q000378:metabolism*; D004347:Drug Interactions / Q000502:physiology; D006801:Humans; D013997:Time Factors
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000959:Antihypertensive Agents; D004077:Digoxin