Biodistribution, tissue reaction, and lung retention of pentamidine aerosolized as three different salts

Aerosolized pentamidine isoethionate is retained in the lung and appears to prevent Pneumocystis carinii pneumonia (PCP) in many AIDS patients. We evaluated alternative formulations of pentamidine that might reduce the airway irritation associated with aerosolized pentamidine isoethionate. Specifically, we assessed the biodistribution, histologic response, and lung retention of the isoethionate, gluconate, and lactate salts of pentamidine after aerosol administration to mice. For each of the three aerosolized salts tested, greater than 50% of the pentamidine initially recovered from the lungs after one dose was still retained there 14 days later. Thus, significant levels of pentamidine, aerosolized as three different salts, are retained in the lung for at least 2 wk after a single dose. The three salts of pentamidine each produced high lung to extrapulmonary drug ratios, the converse of that produced by intravenous injection of pentamidine isoethionate. At very high aerosol doses, the ability of the lung to retain pentamidine appeared saturable. Even aerosolized daily for 2 wk at very high doses, none of the three pentamidine salts produced histologic evidence of organ toxicity. A Phase 1 trial of aerosolized pentamidine gluconate in AIDS-PCP patients is now in progress to determine if this approach can reduce airway irritation.