Abstract
Rolipram (4-(3-Cyclopentyloxy-4-methoxy-phenyl)-2-pyrrolidone) is a novel cAMP-phosphodiesterase inhibitor under clinical investigation as a low dose antidepressant drug. Preclinical toxicity testing was limited by the different degrees of oral bioavailability (BV) of the drug in different animal species. In rats BV was 35% of a 0.2 mg/kg dose, in rabbits 3.6% of a 0.2 mg/ kg dose and in dogs 20% of a 0.1 mg/kg dose. Toxicological studies in dogs could not be performed because the animals vomited even at the human therapeutic dose (about 0.1 mg/kg/d). In Rhesus monkeys doses up to 20 mg/kg could be administered for months without any adverse effects. Because of the extremely low oral BV this dose level resulted in only 1/3 of the bioavailable part of orally administered human therapeutic dose. In order to achieve multiples of drug body burden in test animals as compared with humans, an alternative route of administration was developed by pharmacokinetics. Pilot studies involving different doses, formulations and intervals of subcutaneous injections revealed that s.c. administrations of 1 mg/kg and 10 mg/kg every three days were sufficient to burden the monkeys (cynomolgus) with a single and 10 fold bioavailable human dose, respectively. This newly developed scheme of administration was used for a 1 year systemic tolerance study in cynomolgus monkeys. The study involved three dose levels (1, 3, 10 mg/kg/ 3 d) and plasma level control measurements were performed after 1, 3, 10, 50, and 121 treatments. The results of control measurements were as expected. The present interim results including necropsy in the Cynomolgus monkeys after one year revealed frequent vomiting as the main finding after all tested dosages. This occurred mainly during the first 4 weeks of the treatment period. Besides a slight decrease in the albumin-globulin ratio after 10 mg/kg/3 d no other compound-related changes were observed with regard to hematological, clinical-chemical and organ weight parameters.
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© 1986 Springer-Verlag
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Hümpel, M., Kühne, G., Lehmann, M., Poggel, A. (1986). Pharmacokinetically Governed Design of Animal Toxicity Studies of a New Antidepressant Drug. In: Chambers, C.M., Chambers, P.L., Tuomisto, J. (eds) Toxic Interfaces of Neurones, Smoke and Genes. Archives of Toxicology, vol 9. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-71248-7_37
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DOI: https://doi.org/10.1007/978-3-642-71248-7_37
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-540-16589-7
Online ISBN: 978-3-642-71248-7
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