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Rapid CommunicationShort Communication

Extensive Metabolism of Diltiazem and P-Glycoprotein-Mediated Efflux of Desacetyl-Diltiazem (M1) by Rat Jejunum In Vitro

Espen Molden, Hege Christensen and Reidar Bredo Sund
Drug Metabolism and Disposition February 2000, 28 (2) 107-109;
Espen Molden
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Hege Christensen
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Reidar Bredo Sund
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Abstract

The objective of this in vitro study was to investigate both the intestinal metabolism and transport of diltiazem (DTZ) and its major metabolites in rat jejunum. Metabolism experiments were performed with everted sacs, whereas sheets mounted in a symmetrical twin chamber system were used in transport studies. DTZ was rapidly desacetylated by the rat jejunum to the principle metabolite desacetyl-diltiazem (M1). In addition, minor amounts of N-demethyl-diltiazem and desacetyl-N-demethyl-diltiazem were formed. Due to the rapid desacetylation, it proved difficult to study the transport of DTZ in this model. However, the primary metabolite M1 was shown to be subjected to P-glycoprotein (Pgp)-mediated efflux. The flux rate of M1 was 6- to 7-fold higher from the serosal to the luminal compartment than in the opposite direction. Both coadministration of verapamil and Pgp monoclonal antibody dose dependently increased luminal-to-serosal flux and decreased serosal-to-luminal flux. In conclusion, rat jejunum metabolizes DTZ extensively in vitro, and the major primary metabolite M1 is subjected to Pgp-mediated efflux.

Footnotes

  • Send reprint requests to: Espen Molden, Department of Pharmacology, School of Pharmacy, University of Oslo, P.O. Box 1068 Blindern, N-0316 Oslo, Norway. E-mail: espen.molden{at}farmasi.uio.no

  • ↵2 Deceased.

  • Abbreviations used are::
    DTZ
    diltiazem
    CsA
    cyclosporin A
    MA
    N-demethyl-DTZ
    M2
    desacetyl-N-demethyl-DTZ
    M1
    desacetyl-DTZ
    Pgp
    P-glycoprotein
    PEG
    polyethylene glycol
    • Received March 9, 1999.
    • Accepted October 14, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 28 (2)
Drug Metabolism and Disposition
Vol. 28, Issue 2
1 Feb 2000
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Rapid CommunicationShort Communication

Extensive Metabolism of Diltiazem and P-Glycoprotein-Mediated Efflux of Desacetyl-Diltiazem (M1) by Rat Jejunum In Vitro

Espen Molden, Hege Christensen and Reidar Bredo Sund
Drug Metabolism and Disposition February 1, 2000, 28 (2) 107-109;

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Rapid CommunicationShort Communication

Extensive Metabolism of Diltiazem and P-Glycoprotein-Mediated Efflux of Desacetyl-Diltiazem (M1) by Rat Jejunum In Vitro

Espen Molden, Hege Christensen and Reidar Bredo Sund
Drug Metabolism and Disposition February 1, 2000, 28 (2) 107-109;
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