Tags

Type your tag names separated by a space and hit enter

In vitro identification of the human cytochrome P-450 enzymes involved in the N-demethylation of azelastine.
Drug Metab Dispos. 1999 Aug; 27(8):942-6.DM

Abstract

Azelastine hydrochloride [4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4yl)-1-(2 H)-phthalazinone monohydrochloride], is a long-acting antiallergic and antiasthmatic drug. The human cytochrome P-450 (CYP) isoform responsible for azelastine N-demethylation, the major metabolic pathway for azelastine, has been examined. Eadie-Hofstee plots of azelastine N-demethylation in human liver microsomes were biphasic. In microsomes from baculovirus-infected insect cells, recombinant CYP3A4, 2D6, 1A2, and 2C19 exhibited high azelastine N-demethylase activity. The K(m) values of the recombinant CYP2D6 (3.75 microM) and CYP3A4 (43.7 microM) were relatively close to that of high-affinity (14.1 microM) and low-affinity (54.7 microM) components in human liver microsomes, respectively. Azelastine N-demethylase activity was inhibited only by the anti-CYP3A antibody, in contrast to antibodies for CYP1A, 2D6, and 2C. In addition, desmethylazelastine formation was significantly inhibited by ketoconazole and troleandomycin but only weakly by omeprazole, sulfaphenazole, and furafylline. These observations suggested that the N-demethylation of azelastine is most extensively catalyzed by the CYP2D6 and 3A4 isoforms in humans.

Authors+Show Affiliations

Faculty of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan. iteruko@gpo.kumamoto-u.ac.jpNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

10421623

Citation

Imai, T, et al. "In Vitro Identification of the Human Cytochrome P-450 Enzymes Involved in the N-demethylation of Azelastine." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 27, no. 8, 1999, pp. 942-6.
Imai T, Taketani M, Suzu T, et al. In vitro identification of the human cytochrome P-450 enzymes involved in the N-demethylation of azelastine. Drug Metab Dispos. 1999;27(8):942-6.
Imai, T., Taketani, M., Suzu, T., Kusube, K., & Otagiri, M. (1999). In vitro identification of the human cytochrome P-450 enzymes involved in the N-demethylation of azelastine. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 27(8), 942-6.
Imai T, et al. In Vitro Identification of the Human Cytochrome P-450 Enzymes Involved in the N-demethylation of Azelastine. Drug Metab Dispos. 1999;27(8):942-6. PubMed PMID: 10421623.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In vitro identification of the human cytochrome P-450 enzymes involved in the N-demethylation of azelastine. AU - Imai,T, AU - Taketani,M, AU - Suzu,T, AU - Kusube,K, AU - Otagiri,M, PY - 1999/7/27/pubmed PY - 1999/7/27/medline PY - 1999/7/27/entrez SP - 942 EP - 6 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 27 IS - 8 N2 - Azelastine hydrochloride [4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4yl)-1-(2 H)-phthalazinone monohydrochloride], is a long-acting antiallergic and antiasthmatic drug. The human cytochrome P-450 (CYP) isoform responsible for azelastine N-demethylation, the major metabolic pathway for azelastine, has been examined. Eadie-Hofstee plots of azelastine N-demethylation in human liver microsomes were biphasic. In microsomes from baculovirus-infected insect cells, recombinant CYP3A4, 2D6, 1A2, and 2C19 exhibited high azelastine N-demethylase activity. The K(m) values of the recombinant CYP2D6 (3.75 microM) and CYP3A4 (43.7 microM) were relatively close to that of high-affinity (14.1 microM) and low-affinity (54.7 microM) components in human liver microsomes, respectively. Azelastine N-demethylase activity was inhibited only by the anti-CYP3A antibody, in contrast to antibodies for CYP1A, 2D6, and 2C. In addition, desmethylazelastine formation was significantly inhibited by ketoconazole and troleandomycin but only weakly by omeprazole, sulfaphenazole, and furafylline. These observations suggested that the N-demethylation of azelastine is most extensively catalyzed by the CYP2D6 and 3A4 isoforms in humans. SN - 0090-9556 UR - https://www.unboundmedicine.com/medline/citation/10421623/In_vitro_identification_of_the_human_cytochrome_P_450_enzymes_involved_in_the_N_demethylation_of_azelastine_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=10421623 DB - PRIME DP - Unbound Medicine ER -