![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 27, Issue 12, 1381-1391, December 1999
Division of Drug Metabolism, Azelastine, an antiallergy and antiasthmatic drug, has been
reported to be mainly N-demethylated to
desmethylazelastine in humans. In the present study, Eadie-Hofstee
plots of azelastine N-demethylation in human liver
microsomes were biphasic. In microsomes from human B-lymphoblast cells,
recombinant cytochrome P-450 (CYP)2D6 and CYP1A1 exhibited higher
azelastine N-demethylase activity than did other CYP
enzymes. On the other hand, recombinant CYP3A4 and CYP1A2 as well as
CYP1A1 and CYP2D6 in microsomes from baculovirus-infected insect cells
were active in azelastine N-demethylation. The
KM value of the recombinant CYP2D6 (2.1 µM) from baculovirus-infected insect cells was similar to the
KM value of the high-affinity (2.4 ± 1.3 µM) component in human liver microsomes. On the other hand, the
KM values of the recombinant CYP3A4 (51.1 µM) and CYP1A2 (125.4 µM) from baculovirus-infected insect cells
were similar to the KM value of the
low-affinity (79.7 ± 12.8 µM) component in human liver
microsomes. Bufuralol inhibited the high-affinity component, making the
Eadie-Hofstee plot in human liver microsomes monophasic. Azelastine
N-demethylase activity in human liver microsomes (5 µM
azelastine) was inhibited by ketoconazole, erythromycin, and
fluvoxamine (IC50 = 0.08, 18.2, and 17.2 µM,
respectively). Azelastine N-demethylase activity in
microsomes from twelve human livers was significantly correlated with
testosterone 6
-hydroxylase activity (r = 0.849, p < .0005). The percent contributions of CYP1A2,
CYP2D6, and CYP3A4 in human livers were predicted using several
approaches based on the concept of correction with CYP contents or
relative activity factors (RAFs). Our data suggested that the approach
using RAFCL (RAF as the ratio of clearance) is most
predictive of the N-demethylation clearance of
azelastine because it best reflects the observed
N-demethylation clearance in human liver microsomes.
Summarizing the results, azelastine N-demethylation in
humans liver microsomes is catalyzed mainly by CYP3A4 and CYP2D6, and
CYP1A2 to a small extent (in average, 76.6, 21.8, and 3.9%,
respectively), although the percent contribution of each isoform varied
among individuals.
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics
This article has been cited by other articles:
|
|
 |
|
  S. J. Gardiner and E. J. Begg Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice Pharmacol. Rev., September 1, 2006; 58(3): 521 - 590. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Yamanaka, M. Nakajima, T. Fukami, H. Sakai, A. Nakamura, M. Katoh, M. Takamiya, Y. Aoki, and T. Yokoi CYP2A6 AND CYP2B6 ARE INVOLVED IN NORNICOTINE FORMATION FROM NICOTINE IN HUMANS: INTERINDIVIDUAL DIFFERENCES IN THESE CONTRIBUTIONS Drug Metab. Dispos., December 1, 2005; 33(12): 1811 - 1818. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Nakajima, E. Tanaka, T. Kobayashi, N. Ohashi, T. Kume, and T. Yokoi Imipramine N-Glucuronidation in Human Liver Microsomes: Biphasic Kinetics and Characterization of UDP-Glucuronosyltransferase Isoforms Drug Metab. Dispos., June 1, 2002; 30(6): 636 - 642. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X.-Q. Li, A. Bjorkman, T. B. Andersson, M. Ridderstrom, and C. M. Masimirembwa Amodiaquine Clearance and Its Metabolism to N-Desethylamodiaquine Is Mediated by CYP2C8: A New High Affinity and Turnover Enzyme-Specific Probe Substrate J. Pharmacol. Exp. Ther., February 1, 2002; 300(2): 399 - 407. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Yu and R. L. Haining Comparative Contribution to Dextromethorphan Metabolism by Cytochrome P450 Isoforms in Vitro: Can Dextromethorphan Be Used as a Dual Probe for Both CYP2D6 and CYP3A Activities? Drug Metab. Dispos., November 1, 2001; 29(11): 1514 - 1520. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Komatsu, H. Yamazaki, N. Shimada, M. Nakajima, and T. Yokoi Roles of Cytochromes P450 1A2, 2A6, and 2C8 in 5-Fluorouracil Formation from Tegafur, an Anticancer Prodrug, in Human Liver Microsomes Drug Metab. Dispos., April 13, 2001; 28(12): 1457 - 1463. [Abstract] [Full Text]
|
|
|
|
|
|
K. Venkatakrishnan, L. L. von Moltke, M. H. Court, J. S. Harmatz, C. L. Crespi, and D. J. Greenblatt Comparison between Cytochrome P450 (CYP) Content and Relative Activity Approaches to Scaling from cDNA-Expressed CYPs to Human Liver Microsomes: Ratios of Accessory Proteins as Sources of Discrepancies between the Approaches Drug Metab. Dispos., April 13, 2001; 28(12): 1493 - 1504. [Abstract] [Full Text]
|
|
|
|
|
|
K. Ohyama, M. Nakajima, S. Nakamura, N. Shimada, H. Yamazaki, and T. Yokoi A Significant Role of Human Cytochrome P450 2C8 in Amiodarone N-Deethylation: An Approach to Predict the Contribution with Relative Activity Factor Drug Metab. Dispos., November 1, 2000; 28(11): 1303 - 1310. [Abstract] [Full Text]
|
|
|
|
|
|
D. F. McGinnity, A. J. Parker, M. Soars, and R. J. Riley Automated Definition of the Enzymology of Drug Oxidation by the Major Human Drug Metabolizing Cytochrome P450s Drug Metab. Dispos., November 1, 2000; 28(11): 1327 - 1334. [Abstract] [Full Text]
|
|
|
|
|
|
T. Komatsu, H. Yamazaki, S. Asahi, E. M. J. Gillam, F. P. Guengerich, M. Nakajima, and T. Yokoi Formation of A Dihydroxy Metabolite of Phenytoin in Human Liver Microsomes/cytosol: Roles of Cytochromes P450 2c9, 2c19, and 3a4 Drug Metab. Dispos., November 1, 2000; 28(11): 1361 - 1368. [Abstract] [Full Text]
|
|
|
|
|
|
E. Störmer, L. L. von Moltke, and D. J. Greenblatt Scaling Drug Biotransformation Data from cDNA-Expressed Cytochrome P-450 to Human Liver: A Comparison of Relative Activity Factors and Human Liver Abundance in Studies of Mirtazapine Metabolism J. Pharmacol. Exp. Ther., November 1, 2000; 295(2): 793 - 801. [Abstract] [Full Text]
|
|
 |
 |
 |
|
 |
 |
 |
