JPET Introducing ALZET?ew Model 2006 Pump

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Pauli-Magnus, C.
Right arrow Articles by Fromm, M. F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Pauli-Magnus, C.
Right arrow Articles by Fromm, M. F.

Vol. 293, Issue 2, 376-382, May 2000

Characterization of the Major Metabolites of Verapamil as Substrates and Inhibitors of P-glycoprotein1

Christiane Pauli-Magnus , Oliver von Richter, Oliver Burk, Anja Ziegler, Thomas Mettang, Michel Eichelbaum and Martin F. Fromm

Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany (C.P.-M., O.v.R., O.B., A.Z., M.E., M.F.F.); Division of Internal Medicine, Robert-Bosch-Hospital, Stuttgart, Germany (C.P.-M., T.M.); and Division of Clinical Pharmacology, Eberhard-Karls-University, Tübingen, Germany (M.E.)

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 the N-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.

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

0022-3565/00/2932-0376$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 Drug Metab. Dispos.Home page
K. May, V. Minarikova, K. Linnemann, M. Zygmunt, H. K. Kroemer, C. Fusch, and W. Siegmund
Role of the Multidrug Transporter Proteins ABCB1 and ABCC2 in the Diaplacental Transport of Talinolol in the Term Human Placenta
Drug Metab. Dispos., April 1, 2008; 36(4): 740 - 744.
[Abstract] [Full Text] [PDF]

Home page
 J Clin PharmacolHome page
K.-A. Kim, P.-W. Park, K.-H. Liu, K.-B. Kim, H.-J. Lee, J.-G. Shin, and J.-Y. Park
Effect of Rifampin, an Inducer of CYP3A and P-glycoprotein, on the Pharmacokinetics of Risperidone
J. Clin. Pharmacol., January 1, 2008; 48(1): 66 - 72.
[Abstract] [Full Text] [PDF]

Home page
 Physiol. Rev.Home page
B. Sarkadi, L. Homolya, G. Szakacs, and A. Varadi
Human Multidrug Resistance ABCB and ABCG Transporters: Participation in a Chemoimmunity Defense System.
Physiol Rev, October 1, 2006; 86(4): 1179 - 1236.
[Abstract] [Full Text] [PDF]

Home page
 JNMHome page
A. Takano, H. Kusuhara, T. Suhara, I. Ieiri, T. Morimoto, Y.-J. Lee, J. Maeda, Y. Ikoma, H. Ito, K. Suzuki, et al.
Evaluation of In Vivo P-Glycoprotein Function at the Blood-Brain Barrier Among MDR1 Gene Polymorphisms by Using 11C-Verapamil
J. Nucl. Med., September 1, 2006; 47(9): 1427 - 1433.
[Abstract] [Full Text] [PDF]

Home page
 JNMHome page
Y. Ikoma, A. Takano, H. Ito, H. Kusuhara, Y. Sugiyama, R. Arakawa, T. Fukumura, R. Nakao, K. Suzuki, and T. Suhara
Quantitative Analysis of 11C-Verapamil Transfer at the Human Blood-Brain Barrier for Evaluation of P-glycoprotein Function
J. Nucl. Med., September 1, 2006; 47(9): 1531 - 1537.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
P. Hsiao, L. Sasongko, J. M. Link, D. A. Mankoff, M. Muzi, A. C. Collier, and J. D. Unadkat
Verapamil P-glycoprotein Transport across the Rat Blood-Brain Barrier: Cyclosporine, a Concentration Inhibition Analysis, and Comparison with Human Data
J. Pharmacol. Exp. Ther., May 1, 2006; 317(2): 704 - 710.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
Y.-J. Lee, J. Maeda, H. Kusuhara, T. Okauchi, M. Inaji, Y. Nagai, S. Obayashi, R. Nakao, K. Suzuki, Y. Sugiyama, et al.
In Vivo Evaluation of P-glycoprotein Function at the Blood-Brain Barrier in Nonhuman Primates Using [11C]Verapamil
J. Pharmacol. Exp. Ther., February 1, 2006; 316(2): 647 - 653.
[Abstract] [Full Text] [PDF]

Home page
 BMJHome page
U. Troger, H. Lins, J.-M Scherrmann, C.-W. Wallesch, and S. M Bode-Boger
Tetraparesis associated with colchicine is probably due to inhibition by verapamil of the P-glycoprotein efflux pump in the blood-brain barrier
BMJ, September 17, 2005; 331(7517): 613 - 613.
[Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
O. Burk, K. A. Arnold, A. K. Nussler, E. Schaeffeler, E. Efimova, B. A. Avery, M. A. Avery, M. F. Fromm, and M. Eichelbaum
Antimalarial Artemisinin Drugs Induce Cytochrome P450 and MDR1 Expression by Activation of Xenosensors Pregnane X Receptor and Constitutive Androstane Receptor
Mol. Pharmacol., June 1, 2005; 67(6): 1954 - 1965.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
I. Cascorbi, M. Paul, and H. K. Kroemer
Pharmacogenomics of heart failure - focus on drug disposition and action
Cardiovasc Res, October 1, 2004; 64(1): 32 - 39.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
A. Harrison, A. Betts, K. Fenner, K. Beaumont, A. Edgington, S. Roffey, J. Davis, P. Comby, and P. Morgan
NONLINEAR ORAL PHARMACOKINETICS OF THE {alpha}-ANTAGONIST 4-AMINO-5-(4-FLUOROPHENYL)-6,7-DIMETHOXY-2-[4-(MORPHOLINOCARBONYL)-PERHYDRO-1,4-DIAZEPIN-1-YL]QUINOLINE IN HUMANS: USE OF PRECLINICAL DATA TO RATIONALIZE CLINICAL OBSERVATIONS
Drug Metab. Dispos., February 1, 2004; 32(2): 197 - 204.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
Y.-H. Wang, D. R. Jones, and S. D. Hall
PREDICTION OF CYTOCHROME P450 3A INHIBITION BY VERAPAMIL ENANTIOMERS AND THEIR METABOLITES
Drug Metab. Dispos., February 1, 2004; 32(2): 259 - 266.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
T. Litman, T. Skovsgaard, and W. D. Stein
Pumping of Drugs by P-Glycoprotein: A Two-Step Process?
J. Pharmacol. Exp. Ther., December 1, 2003; 307(3): 846 - 853.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
K. M. M. Doan, J. E. Humphreys, L. O. Webster, S. A. Wring, L. J. Shampine, C. J. Serabjit-Singh, K. K. Adkison, and J. W. Polli
Passive Permeability and P-Glycoprotein-Mediated Efflux Differentiate Central Nervous System (CNS) and Non-CNS Marketed Drugs
J. Pharmacol. Exp. Ther., December 1, 2002; 303(3): 1029 - 1037.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
R. K. Bhardwaj, H. Glaeser, L. Becquemont, U. Klotz, S. K. Gupta, and M. F. Fromm
Piperine, a Major Constituent of Black Pepper, Inhibits Human P-glycoprotein and CYP3A4
J. Pharmacol. Exp. Ther., August 1, 2002; 302(2): 645 - 650.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
S. Ekins, R. B. Kim, B. F. Leake, A. H. Dantzig, E. G. Schuetz, L.-B. Lan, K. Yasuda, R. L. Shepard, M. a Winter, J. D. Schuetz, et al.
Application of Three-Dimensional Quantitative Structure-Activity Relationships of P-Glycoprotein Inhibitors and Substrates
Mol. Pharmacol., May 1, 2002; 61(5): 974 - 981.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
J. W. Polli, S. A. Wring, J. E. Humphreys, L. Huang, J. B. Morgan, L. O. Webster, and C. S. Serabjit-Singh
Rational Use of in Vitro P-glycoprotein Assays in Drug Discovery
J. Pharmacol. Exp. Ther., November 1, 2001; 299(2): 620 - 628.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
J. H. Hochman, M. Chiba, M. Yamazaki, C. Tang, and J. H. Lin
P-glycoprotein-Mediated Efflux of Indinavir Metabolites in Caco-2 Cells Expressing Cytochrome P450 3A4
J. Pharmacol. Exp. Ther., July 1, 2001; 298(1): 323 - 330.
[Abstract] [Full Text]

Home page
 Drug Metab. Dispos.Home page
R. Yumoto, T. Murakami, M. Sanemasa, R. Nasu, J. Nagai, and M. Takano
Pharmacokinetic Interaction of Cytochrome P450 3A-Related Compounds with Rhodamine 123, a P-Glycoprotein Substrate, in Rats Pretreated with Dexamethasone
Drug Metab. Dispos., February 1, 2001; 29(2): 145 - 151.
[Abstract] [Full Text]

Home page
 J. Biol. Chem.Home page
G. da Silva Xavier, A. Varadi, E. K. Ainscow, and G. A. Rutter
Regulation of Gene Expression by Glucose in Pancreatic beta -Cells (MIN6) via Insulin Secretion and Activation of Phosphatidylinositol 3'-Kinase
J. Biol. Chem., November 10, 2000; 275(46): 36269 - 36277.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2000 by the American Society for Pharmacology and Experimental Therapeutics.