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

Abstract

Losartan is a 4-chloro-5-hydroxymethylimidazole derivative that is a potent and highly selective angiotensin II receptor antagonist. Losartan is metabolized in vivo in rats, monkeys, and humans to a carboxylic acid derivative E3174 that is pharmacologically more active than the parent compound. We have investigated the mechanism of this biotransformation in human liver preparations. The oxidation of both losartan and the putative aldehyde intermediate E3179 was catalyzed by the microsomal fraction, required both NADPH and molecular oxygen, and was inhibited by SKF 525-A, implicating cytochrome P450 (CYP). When incubations with each substrate were performed under an atmosphere of 18O2, the extent of 18O incorporation into the carboxylic acid product was consistent with a mechanism for losartan oxidation involving an aldehyde intermediate. To substantiate the involvement of CYP in these reactions, incubations with losartan and the aldehyde E3179 were performed in the presence of isoform-selective inhibitors. Inhibitors of CYP3A4/5 (gestodene and ketoconazole) and CYP2C9/10 (sulfaphenazole) attenuated the oxidation of both substrates. It was then demonstrated that microsomes containing either recombinant human liver CYP2C9 or CYP3A4 were capable of oxidizing both losartan and the aldehyde E3179 to the carboxylic acid E3174. Subsequently, it was shown that rabbit anti-CYP2C9 and anti-CYP3A3/4 inhibited the oxidation of losartan to E3174 in incubations with human liver microsomes. These studies support the hypothesis that the aldehyde E3179 is an intermediate in the oxidation of losartan and that this two-step reaction is catalyzed in human liver microsomes by members of the CYP3A and CYP2C subfamilies.

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  • Authors+Show Affiliations

    ,

    Department of Drug Metabolism I, Merck Research Laboratories RY80L109, Rahway, NJ 07065-0900, USA.

    , ,

    Source

    MeSH

    Adult
    Aged
    Angiotensin Receptor Antagonists
    Antibody Specificity
    Antihypertensive Agents
    Aryl Hydrocarbon Hydroxylases
    B-Lymphocytes
    Biotransformation
    Biphenyl Compounds
    Cell Line
    Chromatography, High Pressure Liquid
    Cytochrome P-450 CYP2C9
    Cytochrome P-450 CYP3A
    Cytochrome P-450 Enzyme System
    Drug Interactions
    Humans
    Imidazoles
    Isoenzymes
    Losartan
    Male
    Microsomes, Liver
    NAD
    NADP
    Oxidation-Reduction
    Oxidoreductases, N-Demethylating
    Oxygen Isotopes
    Recombinant Proteins
    Spectrophotometry, Ultraviolet
    Steroid 16-alpha-Hydroxylase
    Steroid Hydroxylases
    Subcellular Fractions
    Tetrazoles

    Pub Type(s)

    Comparative Study
    Journal Article

    Language

    eng

    PubMed ID

    7736913

    Citation

    Stearns, R A., et al. "Biotransformation of Losartan to Its Active Carboxylic Acid Metabolite in Human Liver Microsomes. Role of Cytochrome P4502C and 3A Subfamily Members." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 23, no. 2, 1995, pp. 207-15.
    Stearns RA, Chakravarty PK, Chen R, 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;23(2):207-15.
    Stearns, R. A., Chakravarty, P. K., Chen, R., & Chiu, S. H. (1995). Biotransformation of losartan to its active carboxylic acid metabolite in human liver microsomes. Role of cytochrome P4502C and 3A subfamily members. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 23(2), pp. 207-15.
    Stearns RA, 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;23(2):207-15. PubMed PMID: 7736913.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Biotransformation of losartan to its active carboxylic acid metabolite in human liver microsomes. Role of cytochrome P4502C and 3A subfamily members. AU - Stearns,R A, AU - Chakravarty,P K, AU - Chen,R, AU - Chiu,S H, PY - 1995/2/1/pubmed PY - 1995/2/1/medline PY - 1995/2/1/entrez SP - 207 EP - 15 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab. Dispos. VL - 23 IS - 2 N2 - Losartan is a 4-chloro-5-hydroxymethylimidazole derivative that is a potent and highly selective angiotensin II receptor antagonist. Losartan is metabolized in vivo in rats, monkeys, and humans to a carboxylic acid derivative E3174 that is pharmacologically more active than the parent compound. We have investigated the mechanism of this biotransformation in human liver preparations. The oxidation of both losartan and the putative aldehyde intermediate E3179 was catalyzed by the microsomal fraction, required both NADPH and molecular oxygen, and was inhibited by SKF 525-A, implicating cytochrome P450 (CYP). When incubations with each substrate were performed under an atmosphere of 18O2, the extent of 18O incorporation into the carboxylic acid product was consistent with a mechanism for losartan oxidation involving an aldehyde intermediate. To substantiate the involvement of CYP in these reactions, incubations with losartan and the aldehyde E3179 were performed in the presence of isoform-selective inhibitors. Inhibitors of CYP3A4/5 (gestodene and ketoconazole) and CYP2C9/10 (sulfaphenazole) attenuated the oxidation of both substrates. It was then demonstrated that microsomes containing either recombinant human liver CYP2C9 or CYP3A4 were capable of oxidizing both losartan and the aldehyde E3179 to the carboxylic acid E3174. Subsequently, it was shown that rabbit anti-CYP2C9 and anti-CYP3A3/4 inhibited the oxidation of losartan to E3174 in incubations with human liver microsomes. These studies support the hypothesis that the aldehyde E3179 is an intermediate in the oxidation of losartan and that this two-step reaction is catalyzed in human liver microsomes by members of the CYP3A and CYP2C subfamilies. SN - 0090-9556 UR - https://www.unboundmedicine.com/medline/citation/7736913/Biotransformation_of_losartan_to_its_active_carboxylic_acid_metabolite_in_human_liver_microsomes__Role_of_cytochrome_P4502C_and_3A_subfamily_members_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=7736913 DB - PRIME DP - Unbound Medicine ER -