Concentrations of aerosolized pentamidine in bronchoalveolar lavage, systemic absorption, and excretion

Abstract

Pentamidine pulmonary pharmacokinetics were studied in 13 patients receiving once-daily inhaled therapy and 4 patients receiving low-dose intravenous treatment for Pneumocystis carinii pneumonia. Twenty-four hours after inhaled or intravenous therapy, the mean (± standard deviation) concentrations of pentamidine in serial bronchoalveolar specimen fluid ranged from 28.6 10 to 177.5 28 ng/ml and 6.05 2.29 to 21.4 15.7 ng/ml, respectively. Pentamidine concentrations in brochoalveolar fluid were generally higher after 2 weeks than after day 1 of therapy; however, the differences were not statistically different (P > 0.05). The pulmonary half-life after inhaled therapy is long; pentamidine was detectable in bronchoalveolar fluid at 33 (one patient), 69 (one patient), and 115 (one patient) days following the completion of 2 weeks of therapy. Systemic absorption of pentamidine was minimal; the mean (± standard deviation) plasma concentration at the completion of inhalation was 13.84 11.8 ng/ml, or 5% of the mean peak plasma concentration achieved after intravenous administration. Accumulation in the plasma did not occur with repeated inhalation as has been described with multiple intravenous dosing. Cumulative urinary excretion 24 h after the first dose was 5% of that observed with intravenous administration. These data may have importance in designing dosage regimens for the further investigation of inhaled pentamidine for treatment or prophylaxis of P. carinii pneumonin.In a pilot study, we reported that either inhaled pentamidine, 4 mg/kg per day, or reduced-dose intravenous pentamidine, 3 mg/kg per day, might be effective therapy for mild Pneumocystis carinii pneumonia (2). In addition, the rate of major adverse reactions with both modes of administration was reduced to approximately 20%. During that study, serial plasma, urine, and bronchoalveolar lavage fluid (BAL) specimens were collected for the determination of pentamidine concentration in the 13 patients who received inhaled therapy, 2 who received intravenous treatment, and 2 subsequent patients not included in the original study who also received intravenous treatment. This report describes the pulmonary pharmacokinetics of pentamidine in these patients. MATERIALS AND METHODS

Primary and secondary metabolism of pentamidine by rats

“…Despite several early studies of the pharmacological properties of the drug (14,16,17,22,23), little was known about the compound. With the development of sensitive and accurate highperformance liquid chromatography (HPLC) assays (1,9,18), more detailed studies on the distribution and pharmacokinetics of pentamidine have been conducted (2,7,8). However, these studies have been performed with the misconception that pentamidine is metabolically inert, a conclusion primarily based on the work of Launoy et al (16,17).…”

Metabolic N-hydroxylation of pentamidine in vitro

“…Four additional putative metabolites were observed, but they have not yet been characterized. While several investigators have commented on the possibility of pentamidine metabolism (2,12,38), this study constitutes the first identification of any metabolites of the drug. * Corresponding author.…”

Low incidence of Pneumocystis carinii pneumonia in HIV patients receiving 300 mg pentamidine aerosol every 2 weeks

“…In patients receiving daily pentamidine inhala tion for treatment of PcP drug levels were deter mined in bronchoalveolar lavage at different time points [1]. There was no significant difference be tween the pentamidine concentration after 1 and 15 days of therapy, suggesting that there is no ac cumulation of pentamidine in the lungs.…”