The accumulation of pentamidine and the toxic effects of the drug, its selected analogues and metabolites on isolated alveolar cells.

Radiolabelled [3H]pentamidine is accumulated into 48-h and 7-day cultures of alveolar epithelial type 2 cells and alveolar macrophages in a linear, time and dose-dependent manner, with the rate of uptake being 15.3, 13.4 and 17.9 pmol/micrograms protein per 30 min, respectively. Uptake was not affected by metabolic inhibitors. The differential toxicity of the parent drug pentamidine, five analogues and six metabolites was assessed on freshly isolated and type 2 cells maintained in culture over 24 h. Toxicity, determined by the attachment ability of alkaline phosphatase positive cells containing lamellar bodies was greater in freshly isolated cells. Overall, three/four of the analogues proved less damaging to type 2 cells than the pentamidine with one derivative [1,3-bis(4-amidino-2-methoxy)propane], a compound particularly efficacious against pneumocystis in rats, showing minimal toxicity. Five metabolites (chain hydroxylated derivatives) were less toxic than the parent drug. However, one metabolite (N,N-dihydroxy derivative) was much more toxic than pentamidine to both type 2 cells and alveolar macrophages. It is concluded that as the type 2 cell can accumulate the drug, it represents a target cell which is particularly sensitive to pentamidine and/or some of its metabolites.

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.

The accumulation of pentamidine into rat lung slices and its interaction with putrescine.

The aromatic diamidine, pentamidine, accumulated into rat lung slices by an uptake system that obeyed saturation kinetics, with an average Km value of 554 microM and a Vmax value of 4077 nmol/g lung wet wt/30 min, respectively. This system was not inhibited by metabolic inhibitors but was greatly diminished by lowering the temperature from 37 degrees to 4 degrees. Both compounds, pentamidine and putrescine, inhibited the uptake of the other and the inhibition of pentamidine accumulation by putrescine was demonstrated to be non-competitive. Uptake of putrescine was inhibited by increasing concentrations of pentamidine. As putrescine accumulates in epithelial type 1 and type 2 cells and in Clara cells, it is likely that pentamidine is also accumulated in these cell types but does not utilize the pulmonary uptake system for polyamine transport. Within the time period studied, toxic effects of the drug were not observed.