Koizumi H, Watanabe M, Numata H, Sakai T, Morishita H
Toxicol Appl Pharmacol. 1986 Jun 15;84(1):125-48. doi: 10.1016/0041-008x(86)90421-7.
A subchronic oral toxicity study of disobutamide, a piperidine ring compound with antiarrhythmic activity, was conducted at doses of 30, 100, and 250 mg/kg in rats, 45 mg/kg in dogs, and 90 mg/kg in monkeys. Numerous vacuoles were observed in various organs such as the liver, kidneys, heart, lungs, spleen, thymus, stomach, and choroid plexus in these animals. The epithelium of the choroid plexus (CP), however, showed severe vacuolation in rats and monkeys but not in dogs. The vacuoles corresponded to enlarged and myelin-figured lysosomes observed by electron microscopy, revealing morphological characteristics which have been reported as drug-induced phospholipidosis. In a further study, the drug penetration to cerebrospinal fluid (CSF) and the drug concentration in CP were examined in these animals. Daily po doses of 250, 45, and 90 mg/kg were, respectively, administered to rats, dogs, and monkeys to maintain approximate equivalency in peak blood concentrations across species, over a course of 35 days. The concentration of the drug in the CP was higher in rats and monkeys than in dogs, and the CSF/serum ratio of the drug concentration was extremely high in rats. The uptake of the drug by the CP in vitro was high in rats, monkeys, and dogs, in this order. In dogs, both direct contact of the drug with the CP during incubation and intraventricular administration induced vacuolation in the epithelium. From these results it was concluded that differences of the drug's penetration into the CSF and its uptake by the choroid plexus epithelium are responsible for the species differences of CP vacuolation in the animals.
对具有抗心律失常活性的哌啶环化合物二丁酰胺进行了亚慢性口服毒性研究，给药剂量分别为大鼠30、100和250mg/kg，犬45mg/kg，猴90mg/kg。在这些动物的肝脏、肾脏、心脏、肺、脾脏、胸腺、胃和脉络丛等多个器官中观察到大量空泡。然而，脉络丛（CP）上皮在大鼠和猴中出现严重空泡化，而在犬中未出现。这些空泡对应于电子显微镜下观察到的增大的、呈髓鞘样的溶酶体，揭示了已报道的药物诱导的磷脂沉积症的形态学特征。在进一步的研究中，检测了这些动物中药物向脑脊液（CSF）的渗透以及CP中的药物浓度。分别给大鼠、犬和猴每日经口给予250、45和90mg/kg的剂量，在35天的过程中维持各物种间血药峰浓度大致相当。大鼠和猴CP中的药物浓度高于犬，且大鼠中药物浓度的CSF/血清比值极高。体外实验中大鼠、猴和犬CP对药物的摄取依次降低。在犬中，孵育期间药物与CP的直接接触以及脑室内给药均诱导上皮出现空泡化。从这些结果得出结论，药物向CSF的渗透及其被脉络丛上皮摄取的差异是导致动物中CP空泡化物种差异的原因。
