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Research ArticleArticle

Evaluation of the Interaction of Loratadine and desloratadine with P-glycoprotein

Er-jia Wang, Christopher N. Casciano, Robert P. Clement and William W. Johnson
Drug Metabolism and Disposition August 2001, 29 (8) 1080-1083;
Er-jia Wang
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Christopher N. Casciano
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Robert P. Clement
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William W. Johnson
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Abstract

The absorption of many drugs is affected by their interaction with ATP-binding cassette (ABC) transporters. The most extensively studied of these ABC transporters is the proein product of MDR1 (multidrug resistance) that encodes a 170-kDa integral plasma membrane phosphorylated glycoprotein known as P-glycoprotein (P-gp). The purpose of this study was to determine, using two different methods, whether the nonsedating antihistamine loratadine (L) and its active metabolite desloratadine (DL) interact with P-gp. MDR cells presenting human P-gp were incubated with the fluorescent P-gp substrate daunorubicin with or without L, DL, and several positive controls. The IC50 of loratadine (∼11 μM) was ∼160 times the maximum observed plasma concentration (Cmax) following a dose of 10 mg. The IC50 of desloratadine (∼43 μM) was ∼880 times the Cmax following a dose of 5 mg. The positive control, cyclosporin A, had an IC50 of ∼1 μM. ATP hydrolysis activity was measured in the membrane fraction prepared from MDR cells presenting P-gp, which were exposed to various concentrations of test compounds. Known substrates of P-gp demonstrated clear, repeatable, concentration-dependent increases in ATP hydrolysis activity. L caused an increase in ATPase activity above basal levels. L had aVmax about 200% basal activity andKm of ∼3 μM for P-gp. In contrast, DL had no significant effect on baseline ATP hydrolysis. L inhibited human P-gp much less than verapamil or cyclosporin A. DL inhibited human P-gp significantly less than L (4 times). DL therefore is not a significant inhibitor of P-gp and should not cause clinical drug interactions with agents that are P-gp substrates.

Footnotes

  • Abbreviations used are::
    L
    loratadine
    MDR
    multidrug resistance
    P-gp
    P-glycoprotein
    ABC
    ATP-binding cassette
    DL
    desloratadine
    • Received December 28, 2000.
    • Accepted April 25, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 29 (8)
Drug Metabolism and Disposition
Vol. 29, Issue 8
1 Aug 2001
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Research ArticleArticle

Evaluation of the Interaction of Loratadine and desloratadine with P-glycoprotein

Er-jia Wang, Christopher N. Casciano, Robert P. Clement and William W. Johnson
Drug Metabolism and Disposition August 1, 2001, 29 (8) 1080-1083;

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Research ArticleArticle

Evaluation of the Interaction of Loratadine and desloratadine with P-glycoprotein

Er-jia Wang, Christopher N. Casciano, Robert P. Clement and William W. Johnson
Drug Metabolism and Disposition August 1, 2001, 29 (8) 1080-1083;
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