Assessment of Radioactive Residues Arising from Radiolabel Instability in a Multiple Dose Tissue Distribution Study in Rats

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概要

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• Our study objectives were: To quantitatively determine the effect of radiolabel instability on terminal phase radioactive tissue residues in a multiple dose tissue distribution study. To quantitatively compare tissue residue artifacts (non drug-related radioactivity) from two chemically-distinct radiolabel locations. To conduct a definitive multiple dose tissue distribution study using the better of the two radiolabeled compounds. We compared the excretion and tissue distribution in rats of [^<14>C] linezolid, radiolabeled in two different locations, after 7 consecutive once daily [^<14>C] oral doses. The radiolabels were in the acetamide (two carbon) and oxazolidinone (isolated carbon) functional groups. Terminal phase tissue residue and excretion data were compared to data from rats dosed orally with [l4C] sodium acetate. Drug-related radioactivity was excreted rapidly over 24 h. After a single dose, the acetamide and oxazolidinone radiolabel sites both gave 3% of dose as exhaled ^<14>CO_2. After 7 daily [^<14>C] oral doses, terminal phase radioactive tissue residues were higher from the acetamide radiolabel, relative to the oxazolidinone radiolabel, and were primarily not drug-related. In the definitive tissue distribution study, low concentrations of drug-related radioactivity in skin and thyroid were observed. We conclude that although small amounts of radiolabel instability do not significantly affect single dose tissue radioactivity C_<max> and AUC, arti facts arising from radiolabel instability can prolong the apparent terminal phase half life and complicate study data interpretation. When possible, it is always preferable to use a completely stable radiolabel site.

• 公益社団法人日本薬学会の論文
• 2003-05-01

著者

• Chiba K

  Discovery Research Laboratories Ii Dainippon Pharmaceutical Company Ltd.

• Courtney Maria

  Global Drug Metabolism Pharmacia Corp.

• Koets Michael

  Global Drug Metabolism Pharmacia Corp.

• Chiba K

  Laboratory Of Bio-organic Chemistry Tokyo University Of Agriculture And Technology

• SLATTER John

  Product Life Cycle Management, Pharmacia Corp.

• SAMS James

  Global Drug Metabolism, Pharmacia Corp.

• EASTER John

  Global Drug Metabolism, Pharmacia Corp.

• FATE Gwendolyn

  Global Drug Metabolism, Pharmacia Corp.

• CHIBA Koji

  Pharmacia K.K.

• JOHNSON Mark

  Global Drug Metabolism, Pharmacia Corp.

• MORRIS Lorrie

  Global Drug Metabolism, Pharmacia Corp.

• Sams James

  Global Drug Metabolism Pharmacia Corp.

• Easter John

  Global Drug Metabolism Pharmacia Corp.

• Johnson Mark

  Global Drug Metabolism Pharmacia Corp.

• Slatter John

  Product Life Cycle Management Pharmacia Corp.

• Morris Lorrie

  Global Drug Metabolism Pharmacia Corp.

• Fate Gwendolyn

  Global Drug Metabolism Pharmacia Corp.

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• Assessment of Radioactive Residues Arising from Radiolabel Instability in a Multiple Dose Tissue Distribution Study in Rats
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