Abstract
Hydroxyimine derivatives of ketoprofen (1) and nabumetone (2) were synthesized and evaluated in vitro and in vivo as cytochrome P450-selective intermediate prodrug structures of ketones. 2 released nabumetone in vitro in the presence of isolated rat and human liver microsomes and in different recombinant human CYP isoforms. Bioconversion of 2 to both nabumetone and its active metabolite, 6-methoxy-2-naphthylacetic acid (6-MNA), was further confirmed in rats in vivo. Results indicate that hydroxyimine is a useful intermediate prodrug structure for ketone drugs.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alanine Transaminase / analysis
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemistry*
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Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics
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Buffers
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Butanones / chemistry
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Butanones / metabolism
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C-Reactive Protein / analysis
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Cytochrome P-450 Enzyme System / chemistry
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Cytochrome P-450 Enzyme System / metabolism*
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Drug Stability
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Humans
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Hydrolysis
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In Vitro Techniques
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Isoenzymes / chemistry
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Isoenzymes / metabolism
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Ketoprofen / chemistry
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Ketoprofen / metabolism
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Male
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Microsomes, Liver / drug effects
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Microsomes, Liver / metabolism
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Nabumetone
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Naphthaleneacetic Acids / metabolism
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Nitric Oxide / biosynthesis
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Nitric Oxide Donors / chemistry*
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Nitric Oxide Donors / pharmacokinetics
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Oximes / chemical synthesis*
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Oximes / chemistry
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Oximes / pharmacokinetics
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Prodrugs / chemical synthesis*
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Prodrugs / chemistry
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Prodrugs / pharmacokinetics
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Rats
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Rats, Wistar
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Serum
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Solubility
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Buffers
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Butanones
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Isoenzymes
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Naphthaleneacetic Acids
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Nitric Oxide Donors
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Oximes
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Prodrugs
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Nitric Oxide
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C-Reactive Protein
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Cytochrome P-450 Enzyme System
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Ketoprofen
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6-methoxy-2-naphthylacetic acid
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Alanine Transaminase
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Nabumetone