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UTILITY OF WHOLE-BODY AUTORADIOLUMINOGRAPHY IN DRUG DISCOVERY FOR THE QUANTIFICATION OF TRITIUM-LABELED DRUG CANDIDATES

Pfizer Inc., Global Research and Development, Pharmacokinetics Dynamics and Metabolism Development, Groton, Connecticut

Whole-body autoradioluminography (WBAL) has evolved as the preferred method for conducting tissue distribution studies that are required for regulatory filings of a new drug entity (DE) and for projecting tissue dosimetry in human mass balance studies. Four experiments were designed to assess WBAL utility using tritium as early as lead development in the drug discovery process. The objective of experiment 1 was to determine the minimum amount of tritium to administer to rats required for obtaining widespread distribution into most tissues at concentrations greater than quantification limits. Experiments 2, 3, and 4 were conducted to identify a tissue compartment responsible for observed triphasic pharmacokinetics, to characterize the distribution of a [³H]DE into brain tissue, and to compare tissue distribution patterns between two rat strains, respectively. The minimum amount of tritium necessary to investigate the tissue distribution of [³H]DE in rats was 865 µCi/kg. Results from experiments 2, 3, and 4 illustrated A) the identification of adipose as the tissue compartment responsible for an extended terminal elimination phase, B) sustained penetration of a DE into brain tissues for at least 24 h, and C) tissue distribution differences between two DEs of the same therapeutic class, respectively. These experiments exemplify the value of WBAL as a screening tool to assist with the selection of a drug candidate. WBAL utilization in drug discovery provides insightful data toward designing pharmacology and toxicology experiments. Substituting the use of tritium for carbon-14 is of crucial importance in drug discovery since [³H]DEs are more readily obtainable than [¹⁴C]DEs.