Vol. 27, Issue 7, 792-797, July 1999

Inhibitory Effects of Azelastine and Its Metabolites on Drug Oxidation Catalyzed by Human Cytochrome P-450 Enzymes

Miki Nakajima, Katsuhiro Ohyama, Sumika Nakamura, Noriaki Shimada, Hiroshi Yamazaki, and Tsuyoshi Yokoi

Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan (M.N., K.O., S.N., H.Y., T.Y.); and Daiichi Pure Chemicals Co., Ltd., Ibaraki, Japan (N.S.)

Azelastine, an antiallergy and antiasthmatic drug, has been reported to be metabolized mainly to desmethylazelastine and 6-hydroxyazelastine in mammals. In the present study, the inhibitory effects of azelastine and its two metabolites on human cytochrome P-450 (CYP) isoform-dependent reactions were investigated to predict the drug interactions of azelastine using microsomes from human B-lymphoblast cells expressing CYP. The specific activities for human CYP isoforms included: 7-ethoxyresorufin O-deethylation (CYP1A1), phenacetin O-deethylation (CYP1A2), coumarin 7-hydroxylation (CYP2A6), 7-benzyloxyresorufin O-dealkylation (CYP2B6), S-warfarin 7-hydroxylation (CYP2C9), S-mephenytoin 4'-hydroxylation (CYP2C19), bufuralol 1'-hydroxylation (CYP2D6), chlorzoxazone 6-hydroxylation (CYP2E1), and testosterone 6-hydroxylation (CYP3A4). In almost all the activities, desmethylazelastine exhibited stronger inhibition than azelastine and 6-hydroxyazelastine. Desmethylazelastine, but not azelastine and 6-hydroxyazelastine, uncompetitively inhibited CYP2B6 activity (K_i = 32.6 ± 4.8 µM). Azelastine, desmethylazelastine, and 6-hydroxyazelastine competitively inhibited CYP2C9 activity (K_i = 13.9 ± 1.8, 15.0 ± 3.1, and 17.0 ± 4.1 µM, respectively), CYP2C19 activity (K_i = 21.9 ± 2.2, 7.3 ± 1.6, and 9.3 ± 1.6 µM, respectively), and CYP2D6 activity (K_i = 1.2 ± 0.1, 1.5 ± 0.2, and 3.0 ± 0.5 µM, respectively). Azelastine and desmethylazelastine competitively inhibited CYP3A4 activity (K_i = 23.7 ± 4.6 and 13.2 ± 2.3 µM). 6-Hydroxyazelastine interfered with the determination of testosterone 6-hydroxylation by HPLC. CYP1A2, CYP2A6, and CYP2E1 activities were not significantly inhibited by azelastine and the two metabolites. Among the human CYPs tested, the inhibitory effects of azelastine and its two metabolites were the most potent on human CYP2D6. In consideration of the K_i values and the concentration of azelastine and desmethylazelastine in human livers after chronic oral administration of azelastine, the possibility of in vivo drug interaction of azelastine and other drugs that are mainly metabolized by CYP2D6 was suggested although it might not cause critical side effects. The inhibition of CYP2C9, CYP2C19, and CYP3A4 activity by azelastine and its two metabolites might be clinically insignificant.