Inhaled cationic amphiphilic drug-induced pulmonary phospholipidosis in rats and dogs: time-course and dose–response of biomarkers of exposure and effect
- 作者：Pauluhn ; Jü ; rgen
- 关键词：Nose-only exposure ; Dosimetry ; Pharmacokinetics ; Tissue binding ; Alveolar macrophages ; Lung overloading
- 刊名：Toxicology
- 出版年：2005
- 期刊代码：47_0300483x
- 类别：pha
- 出版时间：February 1, 2005
- 卷：207
- 期：1
- 页码：59-72
- 文件大小：249 K
摘要
This study compares the pulmonary response to an inhaled highly soluble hydrochloride (CAD-HCl) with a low soluble sulphate salt (CAD-SO4) of a dicationic amphiphilic drug (CAD). These salts are known to accumulate in the lung. The bioavailability through gastrointestinal uptake is poor. Wistar rats and beagle dogs received repeated 1h/day inhalation exposures over 1–4 weeks. The focus of this analysis is to appraise the correlation of markers of effects related to pulmonary phospholipidosis and cytotoxicity relative to the concentration of CAD in the lung tissue, alveolar macrophages and serum. Rats and dogs are known to experience remarkable differences in their respiratory minute volumes and respiratory patterns. In order to facilitate dosimetric comparisons, identical exposure paradigms and methodological procedures were selected. Over a wide range of cumulative dosages, the CADs bound to lung tissue and cells in bronchoalveolar lavage (BAL) paralleled, whilst no clear association existed in terms of plasma concentrations. This suggests that analysis of the fractional loading of BAL-cells (mainly alveolar macrophages) with CAD or CAD-surfactant complexes is amenable to monitor the accumulation of CADs in the lung. In terms of the comparative phospholipidosis-inducing potency, the CAD-HCl was more potent as compared to CAD-SO4. Following dosimetric adjustments, rats and dogs appeared to be equally susceptible to phospholipidosis. In summary, when exposed to equivalent concentrations of CADs, dogs did not demonstrate a markedly different susceptibility than rats. With regard to the relative intensity of changes, the increase of phospholipids in BAL-fluid and especially BAL-cells correlated with the cumulative exposure dose. Thus, with regard to probing the extent of CAD-induced ‘overloading’ of alveolar macrophages pharmacokinetic determinations in BAL-cells are considered superior to determinations in plasma. Additional advantages of using the alveolar macrophage as denominator to normalize pulmonary drug concentrations include comparisons across species, and exposure regimens are feasible based on almost readily available endpoints in both pre-clinical and selected clinical studies.