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Research ArticleArticle

Involvement of CYP2J2 on the Intestinal First-Pass Metabolism of Antihistamine Drug, Astemizole

Shigeki Matsumoto, Tomoe Hirama, Tsutomu Matsubara, Kiyoshi Nagata and Yasushi Yamazoe
Drug Metabolism and Disposition November 2002, 30 (11) 1240-1245; DOI: https://doi.org/10.1124/dmd.30.11.1240
Shigeki Matsumoto
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Tomoe Hirama
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Tsutomu Matsubara
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Kiyoshi Nagata
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Yasushi Yamazoe
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Abstract

Orally administered astemizole is well absorbed but undergoes an extensive first-pass metabolism toO-desmethylastemizole. Desmethylastemizole is formed in the human microsomal systems of the small intestine as well as the liver, which suggests the role of cytochromes P450 (P450s) in the first-pass metabolism of astemizole. Human P450s involved in theO-demethylation of astemizole have, however, not been identified, and the involvement of twelve known drug-metabolizing P450s were denied. During the course of the P450 identification study, higher activities of the astemizole O-demethylation in the rabbit small intestine than in the liver (about 3-fold) were found. These data suggest the possible involvement of CYP2J, since P450 included in this subfamily is dominantly expressed in the small intestine of rabbits. Therefore, CYP2J2 cDNA has been isolated from the human cDNA library and expressed in COS-1 cells. A clear activity of astemizole O-demethylation was detected in recombinant CYP2J2 with Km = 0.65 μM and Vmax = 1129 pmol/nmol P450/min. Expression of the immunoreactive protein with CYP2J2 antibody was detected in the small intestine and liver. Expression levels of the immunoreactive protein with the CYP2J2 antibody in the small intestine were well correlated with the activities of the astemizoleO-demethylation (r = 0.901,n = 5, p < 0.05). The CYP2J2 substrates, arachidonic acid and ebastine, strongly inhibited the microsomal astemizole O-demethylation in the human small intestines and recombinant CYP2J2. These results indicate the involvement of CYP2J2 in the presystemic elimination of astemizole in the human small intestine.

Footnotes

  • Abbreviations used are::
    P450
    cytochrome P450
    LC/MS
    liquid chromatography mass spectrometry
    MS/MS
    tandem mass spectometry
    PCR
    polymerase chain reaction
    HPLC
    high performance liquid chromatography
    • Received April 23, 2002.
    • Accepted August 8, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (11)
Drug Metabolism and Disposition
Vol. 30, Issue 11
1 Nov 2002
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Research ArticleArticle

Involvement of CYP2J2 on the Intestinal First-Pass Metabolism of Antihistamine Drug, Astemizole

Shigeki Matsumoto, Tomoe Hirama, Tsutomu Matsubara, Kiyoshi Nagata and Yasushi Yamazoe
Drug Metabolism and Disposition November 1, 2002, 30 (11) 1240-1245; DOI: https://doi.org/10.1124/dmd.30.11.1240

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Research ArticleArticle

Involvement of CYP2J2 on the Intestinal First-Pass Metabolism of Antihistamine Drug, Astemizole

Shigeki Matsumoto, Tomoe Hirama, Tsutomu Matsubara, Kiyoshi Nagata and Yasushi Yamazoe
Drug Metabolism and Disposition November 1, 2002, 30 (11) 1240-1245; DOI: https://doi.org/10.1124/dmd.30.11.1240
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