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Yasushi Yamazoe - One of the best experts on this subject based on the ideXlab platform.
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in vitro inhibition of human small intestinal and liver microsomal Astemizole o demethylation different contribution of cyp2j2 in the small intestine and liver
Xenobiotica, 2003Co-Authors: Shigeki Matsumoto, Kiyoshi Nagata, T Hirama, Yasushi YamazoeAbstract: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...
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involvement of cyp2j2 on the intestinal first pass metabolism of antihistamine drug Astemizole
Drug Metabolism and Disposition, 2002Co-Authors: Shigeki Matsumoto, Tomoe Hirama, Tsutomu Matsubara, Kiyoshi Nagata, Yasushi YamazoeAbstract: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
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Involvement of CYP2J2 on the intestinal first-pass metabolism of antihistamine drug, Astemizole.
Drug Metabolism and Disposition, 2002Co-Authors: Shigeki Matsumoto, Tomoe Hirama, Tsutomu Matsubara, Kiyoshi Nagata, Yasushi YamazoeAbstract: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.
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involvement of multiple human cytochromes p450 in the liver microsomal metabolism of Astemizole and a comparison with terfenadine
British Journal of Clinical Pharmacology, 2001Co-Authors: Shigeki Matsumoto, Yasushi YamazoeAbstract:Aims The aims of the present study were to investigate the metabolism of Astemizole in human liver microsomes, to assess possible pharmacokinetic drug-interactions with Astemizole and to compare its metabolism with terfenadine, a typical H1 receptor antagonist known to be metabolized predominantly by CYP3A4. Methods Astemizole or terfenadine were incubated with human liver microsomes or recombinant cytochromes P450 in the absence or presence of chemical inhibitors and antibodies. Results Troleandomycin, a CYP3A4 inhibitor, markedly reduced the oxidation of terfenadine (26% of controls) in human liver microsomes, but showed only a marginal inhibition on the oxidation of Astemizole (81% of controls). Three metabolites of Astemizole were detected in a liver microsomal system, i.e. desmethylAstemizole (DES-AST), 6-hydroxyAstemizole (6OH-AST) and norAstemizole (NOR-AST) at the ratio of 7.4 : 2.8 : 1. Experiments with recombinant P450s and antibodies indicate a negligible role for CYP3A4 on the main metabolic route of Astemizole, i.e. formation of DES-AST, although CYP3A4 may mediate the relatively minor metabolic routes to 6OH-AST and NOR-AST. Recombinant CYP2D6 catalysed the formation of 6OH-AST and DES-AST. Studies with human liver microsomes, however, suggest a major role for a mono P450 in DES-AST formation. Conclusions In contrast to terfenadine, a minor role for CYP3A4 and involvement of multiple P450 isozymes are suggested in the metabolism of Astemizole. These differences in P450 isozymes involved in the metabolism of Astemizole and terfenadine may associate with distinct pharmacokinetic influences observed with coadministration of drugs metabolized by CYP3A4.
Shigeki Matsumoto - One of the best experts on this subject based on the ideXlab platform.
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in vitro inhibition of human small intestinal and liver microsomal Astemizole o demethylation different contribution of cyp2j2 in the small intestine and liver
Xenobiotica, 2003Co-Authors: Shigeki Matsumoto, Kiyoshi Nagata, T Hirama, Yasushi YamazoeAbstract: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...
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involvement of cyp2j2 on the intestinal first pass metabolism of antihistamine drug Astemizole
Drug Metabolism and Disposition, 2002Co-Authors: Shigeki Matsumoto, Tomoe Hirama, Tsutomu Matsubara, Kiyoshi Nagata, Yasushi YamazoeAbstract: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
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Involvement of CYP2J2 on the intestinal first-pass metabolism of antihistamine drug, Astemizole.
Drug Metabolism and Disposition, 2002Co-Authors: Shigeki Matsumoto, Tomoe Hirama, Tsutomu Matsubara, Kiyoshi Nagata, Yasushi YamazoeAbstract: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.
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involvement of multiple human cytochromes p450 in the liver microsomal metabolism of Astemizole and a comparison with terfenadine
British Journal of Clinical Pharmacology, 2001Co-Authors: Shigeki Matsumoto, Yasushi YamazoeAbstract:Aims The aims of the present study were to investigate the metabolism of Astemizole in human liver microsomes, to assess possible pharmacokinetic drug-interactions with Astemizole and to compare its metabolism with terfenadine, a typical H1 receptor antagonist known to be metabolized predominantly by CYP3A4. Methods Astemizole or terfenadine were incubated with human liver microsomes or recombinant cytochromes P450 in the absence or presence of chemical inhibitors and antibodies. Results Troleandomycin, a CYP3A4 inhibitor, markedly reduced the oxidation of terfenadine (26% of controls) in human liver microsomes, but showed only a marginal inhibition on the oxidation of Astemizole (81% of controls). Three metabolites of Astemizole were detected in a liver microsomal system, i.e. desmethylAstemizole (DES-AST), 6-hydroxyAstemizole (6OH-AST) and norAstemizole (NOR-AST) at the ratio of 7.4 : 2.8 : 1. Experiments with recombinant P450s and antibodies indicate a negligible role for CYP3A4 on the main metabolic route of Astemizole, i.e. formation of DES-AST, although CYP3A4 may mediate the relatively minor metabolic routes to 6OH-AST and NOR-AST. Recombinant CYP2D6 catalysed the formation of 6OH-AST and DES-AST. Studies with human liver microsomes, however, suggest a major role for a mono P450 in DES-AST formation. Conclusions In contrast to terfenadine, a minor role for CYP3A4 and involvement of multiple P450 isozymes are suggested in the metabolism of Astemizole. These differences in P450 isozymes involved in the metabolism of Astemizole and terfenadine may associate with distinct pharmacokinetic influences observed with coadministration of drugs metabolized by CYP3A4.
Marshall S Stanton - One of the best experts on this subject based on the ideXlab platform.
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torsades de pointes ventricular tachycardia associated with overdose of Astemizole
Mayo Clinic Proceedings, 1994Co-Authors: Arun Adlakha, Bikram Vermaansil, Thomas D Meloy, Marshall S StantonAbstract: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).
Kiyoshi Nagata - One of the best experts on this subject based on the ideXlab platform.
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in vitro inhibition of human small intestinal and liver microsomal Astemizole o demethylation different contribution of cyp2j2 in the small intestine and liver
Xenobiotica, 2003Co-Authors: Shigeki Matsumoto, Kiyoshi Nagata, T Hirama, Yasushi YamazoeAbstract: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...
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involvement of cyp2j2 on the intestinal first pass metabolism of antihistamine drug Astemizole
Drug Metabolism and Disposition, 2002Co-Authors: Shigeki Matsumoto, Tomoe Hirama, Tsutomu Matsubara, Kiyoshi Nagata, Yasushi YamazoeAbstract: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
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Involvement of CYP2J2 on the intestinal first-pass metabolism of antihistamine drug, Astemizole.
Drug Metabolism and Disposition, 2002Co-Authors: Shigeki Matsumoto, Tomoe Hirama, Tsutomu Matsubara, Kiyoshi Nagata, Yasushi YamazoeAbstract: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.
Florence Dixmerias - One of the best experts on this subject based on the ideXlab platform.
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prolonged qt interval and torsade de pointes following Astemizole overdose
Clinical Toxicology, 1993Co-Authors: Philippe Saviuc, Vincent Danel, Florence DixmeriasAbstract:AbstractA 26 year-old woman was admitted to the hospital two hours after Astemizole overdose. Electrocardiograph showed a prolonged QT interval. Torsade de pointes occurred 13 h after ingestion. Plasma levels of Astemizole plus hydroxylated metabolites showed an apparent plasma half-life of 17 h. The possible occurrence of torsade de pointes in Astemizole overdose, and the long elimination time of Astemizole and hydroxylated metabolites, makes it necessary to maintain ECG monitoring until QT interval has returned to normal.
