Regular Article
Inhibitory Effects of Angiotensin Receptor Blockers on CYP2C9 Activity in Human Liver Microsomes

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Summary:

We investigated the inhibitory effects of the angiotensin receptor blockers (ARBs), candesartan, irbesartan, losartan, losartan active metabolite (EXP-3174), olmesartan, telmisartan and valsartan (0.3-300 μM), on the CYP2C9 activity in human liver microsomes using (S)-( — )-warfarin as a typical CYP2C9 substrate.

Except for olmesartan and valsartan, these ARBs inhibited the activity of 7-hydroxylation of (S)-( — )-warfarin with IC50 values of 39.5-116 μM. Of six synthetic derivatives of olmesartan, five compounds which possess either alkyl groups or a chloro group at the same position as that of the hydroxyisopropyl group in olmesartan inhibited CYP2C9 activity with IC50 values of 21.7-161 μM. Olmesartan and the olmesartan analogue, RNH-6272, both having a hydroxyisopropyl group, showed no inhibition, indicating that the hydrophilicity of this group greatly contributes to the lack of CYP2C9 inhibition by these two compounds. A three-dimensional model for docking between EXP-3174 and CYP2C9 indicated that the chloro group of EXP-3174 is oriented to a hydrophobic pocket in the CYP2C9 active site, indicating that the lipophilicity of the group present in ARBs at the position corresponding to that of the hydroxyisopropyl group in olmesartan is important in inhibiting CYP2C9 activity.

References (23)

  • M.R. Wester et al.

    The structure of human cytochrome P450 2C9 complexed with flurbiprofen at 2.0-Å resolution

    J. Biol. Chem.

    (2004)
  • D.F.V. Lewis et al.

    Compound lipophilicity for substrate binding to human P450s in drug metabolism

    Drug Discovery Today

    (2004)
  • H. Mori et al.

    Current status of antihypertensive prescription and associated blood pres sure control in Japan

    Hypertens. Res.

    (2006)
  • J. Earl

    Cardium Study #58 Hypertension October 2004

  • Z.H. Israili

    Clinical pharmacokinetics of angiotensin II (AT1) receptor blockers in hypertension

    J. hum. Hypertens.

    (2000)
  • T. Unger et al.

    Drug interactions with angiotensin receptor blockers: A comparison with other antihypertensives

    Drug Safety

    (2003)
  • B. Schmidt et al.

    Angiotensin II AT1 receptor antagonists. Clinical implications of active metabolites

    J. Med. Chem.

    (2003)
  • J.O. Miners et al.

    Cytochrome P4502C9: an enzyme of major importance in human drug metabolism

    Br. J. Clin. Pharmacol.

    (1998)
  • R.A. Steans et al.

    Biotransformation of losartan to its active carboxylic acid metabolite in human liver microsomes. Role of cytochrome P4502C and 3A subfamily members

    Drug Metab. Dispos.

    (1995)
  • Ü. Easar et al.

    Role of CYP2C9 polymorphism in losartan oxidation

    Drug Metab. Dispos.

    (2001)
  • M. Bourrié et al.

    Role of cytochrome P-4502C9 in irbesartan oxidation by human liver microsomes

    Drug Metab. Disps.

    (1999)
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