Ruben Z, Dodd D C, Rorig K J, Anderson S N
Research and Development, G. D. Searle & Company, Skokie, Illinois 60077.
Toxicol Appl Pharmacol. 1989 Jan;97(1):57-71. doi: 10.1016/0041-008x(89)90055-0.
Disobutamide, a bis tertiary amine (pKa1 = 8.6; pKa2 = 10.2) cationic amphiphilic compound, and a putative cardiac antiarrhythmic drug induced clear cytoplasmic vacuoles in dogs and rats. Ultrastructurally, the vacuoles were membrane-bound vesicles containing primarily electron-lucent material. Some concentric lamellar bodies indicative of phospholipidosis were also present. Although numerous vacuoles were seen in one-year toxicity studies in dogs and rats, there was no apparent evidence of necrosis, inflammation, atrophy, hypoplasia, hyperplasia, or metaplasia. Clinical signs or laboratory findings indicative of functional impairment were also not apparent. The picture of the vacuolation in vivo was one of storage. In cultured cells vacuoles were shown to be storage sites for disobutamide and specifically in distended vesicles of the cytoplasmic acidic compartments, such as lysosomes, endocytic, and probably transport vesicles. Storage of the drug in acidic vesicles is compatible with the dibasic nature of the cationic moiety of disobutamide. The intrinsic cell chemicals which accumulate in the vacuoles along with disobutamide remain unknown. Disobutamide may be a useful agent for defining experimentally the borderline between physiologic limits (normal function) and toxicity (functional impairment) in the condition of intracellular drug storage abnormalities and for advancing knowledge of storage mechanisms.
双丁酰胺是一种双叔胺（pKa1 = 8.6；pKa2 = 10.2）阳离子两亲性化合物，作为一种假定的心脏抗心律失常药物，可在犬和大鼠体内诱导明显的细胞质空泡形成。超微结构上，这些空泡是膜结合的囊泡，主要含有电子透明物质。还存在一些提示磷脂沉积症的同心层状体。尽管在犬和大鼠的一年毒性研究中观察到大量空泡，但没有明显的坏死、炎症、萎缩、发育不全、增生或化生证据。也没有明显的临床体征或实验室检查结果提示功能受损。体内空泡化的表现是一种储存现象。在培养细胞中，空泡被证明是双丁酰胺的储存位点，特别是在细胞质酸性区室（如溶酶体、内吞小泡以及可能的转运小泡）扩张的囊泡中。药物在酸性小泡中的储存与双丁酰胺阳离子部分的二元性质相符。与双丁酰胺一起积聚在空泡中的内在细胞化学物质仍不清楚。双丁酰胺可能是一种有用的药物，可用于通过实验确定细胞内药物储存异常情况下生理极限（正常功能）和毒性（功能受损）之间的界限，并推进对储存机制的认识。
