Species differences in vacuolation of the choroid plexus induced by the piperidine-ring drug disobutamide in the rat, dog, and monkey |
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| Authors: | H Koizumi M Watanabe H Numata T Sakai H Morishita |
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| Affiliation: | 1. Eli Lilly and Company, Indianapolis, IN, United States;2. Auburn University, Auburn, AL, United States;3. Charles River Laboratories, Reno, NV, United States;1. Neurobehavioral Sciences Department, United States;2. Safety Pharmacology Department, United States;3. Drug Safety Assessment, United States;1. Laboratório de Genética e Cardiologia Molecular, Instituto do Coração (InCor), Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil;2. Departamento de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil;3. Unidade de Cardiogeriatria, Instituto do Coração (InCor), Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil;4. Academic Research Organization (ARO), Hospital Israelita Albert Eistein, São Paulo, São Paulo, Brazil;1. Department of Analytical Chemistry, Faculty of Pharmacy, Misr International University (MIU), Km 28 Ismailia Road, Orabi District, Cairo, Egypt;2. Laboratory for Single Cell Mass Spectrometry, Center for Biosystems Dynamics Research (BDR), RIKEN, 6-2-3 Furuedai, Suita, Osaka 565-0874, Japan;3. Research Center, Misr International University, Km 28 Ismailia Road, Cairo, Egypt;4. Laboratory for Cell-Free Protein Synthesis, Center for Biosystems Dynamics Research (BDR), RIKEN, 6-2-3 Furuedai, Suita, Osaka 565-0874, Japan;5. Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt;1. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El Aini st., 11562 Cairo, Egypt;2. Department of Biochemistry, Faculty of Pharmacy, Cairo University, Kasr El Aini st., 11562 Cairo, Egypt;3. Biochemistry Division and GTMR Unit, Department of Pharmacology and Toxicology, Faculty of Pharmacy, Taif University, Taif, Saudi Arabia;4. School of Pharmacy, Newgiza University, Cairo, Egypt |
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| Abstract: | ![]()
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. |
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