Dose-dependent distribution of 3H-pentamidine following intra-tracheal administration to rats

1. The acute toxicity to the lung, and disposition, of pentamidine isethionate as a function of a pulmonary-delivered dose was investigated in the rat. 2. Acute toxicity 24 h following intra-tracheal instillation of pentamidine was determined by analysis of acellular surface protein concentration and differential cell counting of bronchoalveolar lavage fluid. These two parameters indicated that pentamidine doses > 10 mg/kg lead to increasingly severe oedematous and inflammatory responses within the lung. 3. Following intra-tracheal administration of sub-toxic doses of 3H-pentamidine (0.2-10 mg/kg), the extent of activity in liver, kidney, gut and lavage fluid at 24 h correlated significantly with dose, whereas the level of activity in lung was saturated at doses > 0.8 mg/kg. 4. Values of << 1 for liver:lung and kidney:lung ratios of 3H-activity at low pentamidine doses demonstrated the high affinity of the lung for the compound. These ratios substantially increased with pentamidine dose, reflecting distribution of the drug to liver and kidney. Association of radioactivity with these organs was rapid (< 30 min), and indicated that pentamidine is effectively absorbed from the respiratory tract following intra-tracheal instillation.