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Astemizole

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Yasushi Yamazoe – 1st expert on this subject based on the ideXlab platform

  • in vitro inhibition of human small intestinal and liver microsomal Astemizole o demethylation different contribution of cyp2j2 in the small intestine and liver
    Xenobiotica, 2003
    Co-Authors: Shigeki Matsumoto, Kiyoshi Nagata, T Hirama, Yasushi Yamazoe

    Abstract:

    1. The effects of chemical agents on the metabolism of the antihistamine drug Astemizole were investigated to evaluate drug-drug interactions. 2. Chemical inhibitors of Astemizole O -demethylation were screened using the small intestinal and liver microsomes from rabbit as an animal model for the first-pass metabolism of humans. In the rabbit small intestine, Astemizole O -demethylation was clearly inhibited by ebastine, arachidonic acid, α -naphthoflavone, ketoconazole, tranylcypromine, troglitazone and terfenadine. 3. In humans, these inhibitors also reduced microsomal Astemizole O -demethylation in both the small intestine and liver. However, the inhibition rate of almost all these chemicals were clearly greater in the small intestine than in the liver. Thus, a different contribution of cytochrome P450 in each tissue is suggested. 4. All the chemicals inhibited Astemizole O -demethylation in recombinant CYP2J2 microsomes. The results suggest that CYP2J2 is involved in Astemizole O -demethylation in bot…

  • involvement of cyp2j2 on the intestinal first pass metabolism of antihistamine drug Astemizole
    Drug Metabolism and Disposition, 2002
    Co-Authors: Shigeki Matsumoto, Tomoe Hirama, Tsutomu Matsubara, Kiyoshi Nagata, Yasushi Yamazoe

    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

  • Involvement of CYP2J2 on the intestinal first-pass metabolism of antihistamine drug, Astemizole.
    Drug Metabolism and Disposition, 2002
    Co-Authors: Shigeki Matsumoto, Tomoe Hirama, Tsutomu Matsubara, Kiyoshi Nagata, Yasushi Yamazoe

    Abstract:

    Orally administered Astemizole is well absorbed but undergoes an extensive first-pass metabolism to O -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 the O -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 K m = 0.65 μM and V max = 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 Astemizole O -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.

Shigeki Matsumoto – 2nd expert on this subject based on the ideXlab platform

  • in vitro inhibition of human small intestinal and liver microsomal Astemizole o demethylation different contribution of cyp2j2 in the small intestine and liver
    Xenobiotica, 2003
    Co-Authors: Shigeki Matsumoto, Kiyoshi Nagata, T Hirama, Yasushi Yamazoe

    Abstract:

    1. The effects of chemical agents on the metabolism of the antihistamine drug Astemizole were investigated to evaluate drug-drug interactions. 2. Chemical inhibitors of Astemizole O -demethylation were screened using the small intestinal and liver microsomes from rabbit as an animal model for the first-pass metabolism of humans. In the rabbit small intestine, Astemizole O -demethylation was clearly inhibited by ebastine, arachidonic acid, α -naphthoflavone, ketoconazole, tranylcypromine, troglitazone and terfenadine. 3. In humans, these inhibitors also reduced microsomal Astemizole O -demethylation in both the small intestine and liver. However, the inhibition rate of almost all these chemicals were clearly greater in the small intestine than in the liver. Thus, a different contribution of cytochrome P450 in each tissue is suggested. 4. All the chemicals inhibited Astemizole O -demethylation in recombinant CYP2J2 microsomes. The results suggest that CYP2J2 is involved in Astemizole O -demethylation in bot…

  • involvement of cyp2j2 on the intestinal first pass metabolism of antihistamine drug Astemizole
    Drug Metabolism and Disposition, 2002
    Co-Authors: Shigeki Matsumoto, Tomoe Hirama, Tsutomu Matsubara, Kiyoshi Nagata, Yasushi Yamazoe

    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

  • Involvement of CYP2J2 on the intestinal first-pass metabolism of antihistamine drug, Astemizole.
    Drug Metabolism and Disposition, 2002
    Co-Authors: Shigeki Matsumoto, Tomoe Hirama, Tsutomu Matsubara, Kiyoshi Nagata, Yasushi Yamazoe

    Abstract:

    Orally administered Astemizole is well absorbed but undergoes an extensive first-pass metabolism to O -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 the O -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 K m = 0.65 μM and V max = 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 Astemizole O -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.

Marshall S Stanton – 3rd expert on this subject based on the ideXlab platform

  • torsades de pointes ventricular tachycardia associated with overdose of Astemizole
    Mayo Clinic Proceedings, 1994
    Co-Authors: Arun Adlakha, Bikram Vermaansil, Thomas D Meloy, Marshall S Stanton

    Abstract:

    An overdose of Astemizole predisposes the myocardium to ventricular dysrhythmias, including torsades de pointes. Herein we describe a case of Astemizole-induced torsades de pointes ventricular tachycardia and also review previous case reports in the literature. All the patients were young, and dysrhythmias developed only in those with corrected QT intervals greater than 500 ms. Although several mechanisms have been postulated, no clear explanation has been provided for why Astemizole promotes myocardial dysrhythmias. Treatment of Astemizole-induced torsades de pointes includes discontinuing use of Astemizole, intravenous administration of magnesium sulfate and isoproterenol, temporary cardiac pacing, and, when necessary, direct current cardioversion. A cardiac cause of syncope or convulsions must not be overlooked, especially in patients taking H 1 antagonists because they often have these symptoms before hospitalization or detection of torsades de pointes (or both).