title: Interaction of digoxin with antihypertensive drugs via MDR1.
abstract: 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.
authors.affiliation: Department of Hospital Pharmacy, School of Medicine, Kobe University, Japan.
authors.forename: Kohji
authors.initials: K
authors.lastname: Takara
authors.forename: Mikio
authors.initials: M
authors.lastname: Kakumoto
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Tanigawara
authors.forename: Junko
authors.initials: J
authors.lastname: Funakoshi
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakaeda
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Okumura
mesh_terms: 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
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000959:Antihypertensive Agents; D004077:Digoxin