特異体質性の薬物毒性―薬物動態学的視点―

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書誌事項

タイトル別名
  • Idiosyncratic Drug Toxicity-View from Pharmacokinetics and Drug Metabolism-
  • トクイ タイシツセイ ノ ヤクブツ ドクセイ ヤクブツ ドウタイガクテキ シテン
  • —View from Pharmacokinetics and Drug Metabolism—
  • —薬物動態学的視点—

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Idiosyncratic drug toxicity is a rare, toxic drug reaction found only in the drug-treated patients clinically, and is not reproducible in animal experiments. In many cases, this toxicity is initiated quite likely by a production of chemically reactive metabolites, which covalently bind to macromolecules such as proteins and nucleic acids unless otherwise detoxified by glutathione S-transferases or other scavenging enzymes. Drug-modified proteins, particularly those present in the supernatant fraction, are generally processed to peptide fragments by a proteasome. These peptides are transported to the cell surface after binding to the major histocompatibility complex class I (MHC-I), and presented to the immune system. It is believed that abnormal peptides, when recognized by cytotoxic T-lymphocytes as non-self peptides, induce the toxic immune reaction finally leading to the cell death. Idiosyncrasy would reside on 1) production of the chemically reactive metabolites, 2) degradation of the reactive metabolites, and 3) recognition of drug-modified proteins as non-self proteins by the immune system. In order to prevent the idiosyncratic drug toxicity, organic chemists need to establish a strategy donating the structural nature being hardly converted to the reactive forms to the drug molecules. To detect the chemically reactive metabolites, highly sensitive detection of glutathione conjugate, produced by incubating the parent drug with liver microsomes in the presence of NADPH and glutathione, by a neutral loss scan set at 129 using LC/MS/MS could be utilized. A high pharmacological potency of the drug that eventually leads to a reduced dose level not higher than 10 mg/body would be another avenue to circumvent the idiosyncratic drug toxicity.

収録刊行物

  • 質量分析

    質量分析 53 (3), 142-145, 2005

    一般社団法人 日本質量分析学会

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