P-glycoprotein-mediated transport of digitoxin, alpha-methyldigoxin and beta-acetyldigoxin

Digoxin is a drug with a narrow therapeutic index, which is substrate of th e ATP-dependent efflux pump P-glycoprotein. Increased or decreased digoxin plasma concentrations occur in humans due to inhibition or induction of thi s drug transporter in organs with excretory function such as small intestin e, liver and kidneys. Whereas particle size, dissolution rate and lipophili c properties have been identified as determinants for absorption of digital is glycosides, little is known about P-glycoprotein transport characteristi cs of digitalis glycosides such as digitoxin, alpha -methyldigoxin, beta -a cetyldigoxin and ouabain. Using polarized P-glycoprotein-expressing cell li nes we therefore studied whether these compounds are substrates of P-glycop rotein. Polarized transport of digitalis glycosides was assessed in P-glycoprotein- expressing Caco-2 and L-MDR1 cells (LLC-PK1 cells stably transfected with t he human MDR1 P-glycoprotein). Inhibition of P-glycoprotein-mediated transp ort of these compounds in Caco-2 cells was determined using the cyclosporin e analogue PSC-833 (valspodar) as inhibitor of P-glycoprotein.