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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Characterization of the Major Metabolites of Verapamil as Substrates and Inhibitors of P-glycoprotein

Christiane Pauli-Magnus, Oliver von Richter, Oliver Burk, Anja Ziegler, Thomas Mettang, Michel Eichelbaum and Martin F. Fromm
Journal of Pharmacology and Experimental Therapeutics May 2000, 293 (2) 376-382;
Christiane Pauli-Magnus
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Oliver von Richter
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Oliver Burk
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Anja Ziegler
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Thomas Mettang
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Michel Eichelbaum
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Martin F. Fromm
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Abstract

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.

Footnotes

  • Send reprint requests to: Martin F. Fromm, M.D., Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstr. 112, 70376 Stuttgart, Germany. E-mail:martin.fromm{at}ikp-stuttgart.de

  • ↵1 This work was supported by the Robert-Bosch Foundation (Stuttgart, Germany) and the Khalil Foundation.

  • Abbreviation:
    Papp
    apparent permeability coefficient
    • Received October 7, 1999.
    • Accepted January 19, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 293 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 293, Issue 2
1 May 2000
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Characterization of the Major Metabolites of Verapamil as Substrates and Inhibitors of P-glycoprotein

Christiane Pauli-Magnus, Oliver von Richter, Oliver Burk, Anja Ziegler, Thomas Mettang, Michel Eichelbaum and Martin F. Fromm
Journal of Pharmacology and Experimental Therapeutics May 1, 2000, 293 (2) 376-382;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Characterization of the Major Metabolites of Verapamil as Substrates and Inhibitors of P-glycoprotein

Christiane Pauli-Magnus, Oliver von Richter, Oliver Burk, Anja Ziegler, Thomas Mettang, Michel Eichelbaum and Martin F. Fromm
Journal of Pharmacology and Experimental Therapeutics May 1, 2000, 293 (2) 376-382;
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