RT Journal Article
SR Electronic
T1 Characterization of the Major Metabolites of Verapamil as Substrates and Inhibitors of P-glycoprotein
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 376
OP 382
VO 293
IS 2
A1 Christiane Pauli-Magnus
A1 Oliver von Richter
A1 Oliver Burk
A1 Anja Ziegler
A1 Thomas Mettang
A1 Michel Eichelbaum
A1 Martin F. Fromm
YR 2000
UL http://jpet.aspetjournals.org/content/293/2/376.abstract
AB Verapamil is subject to extensive oxidative metabolism mediated by cytochrome P450 enzymes with less than 5% of an oral dose being excreted unchanged in urine. Furthermore, verapamil is known to be a potent inhibitor of P-glycoprotein function. There is evidence from in vivo investigations that some verapamil metabolites might be actively transported. The aim of the present study was to investigate P-glycoprotein-mediated transport and inhibition properties of verapamil and its metabolites norverapamil, D-620, D-617, and D-703. Polarized transport of these compounds was assessed in P-glycoprotein-expressing Caco-2 and L-MDR1 cells (LLC-PK1 cells stably transfected with human MDR1-P-glycoprotein). Inhibition of P-glycoprotein-mediated transport by these compounds was determined using digoxin as P-glycoprotein substrate. At concentrations of 5 μM, significant differences between basal-to-apical and apical-to-basal apparent permeability coefficients were observed for D-617 and D-620 in all P-glycoprotein-expressing cell monolayers, indicating that both are P-glycoprotein substrates. In contrast, no P-glycoprotein-dependent transport was found for verapamil, norverapamil, and D-703 in Caco-2 cells and for D-703 in L-MDR1 cells. Moreover, verapamil, norverapamil, and D-703 inhibited P-glycoprotein-mediated digoxin transport with IC50 values of 1.1, 0.3, and 1.6 μM, respectively, whereas D-617 and D-620 did not (at concentrations up to 100 μM). We conclude that verapamil phase I metabolites exhibit different P-glycoprotein substrate and inhibition characteristics, with theN-dealkylated metabolites D-617 and D-620 being P-glycoprotein substrates and norverapamil and D-703 being inhibitors of P-glycoprotein function, which may influence P-glycoprotein-dependent drug disposition and elimination. The American Society for Pharmacology and Experimental Therapeutics