title: Absorption, elimination and cerebrospinal fluid concentrations of nimodipine in healthy beagle dogs receiving human intravenous and oral formulation.
abstract: Nimodipine is an L-type calcium channel blocker and is used to treat vasospasm in patients with subarachnoid hemorrhage. Its putative mechanism of action is relaxation of smooth muscle cells in cerebral arteries. In addition, nimodipine may have pleiotropic effects against vasospasm. Systemic hypotension is an adverse effect when patients are treated with oral or intravenous nimodipine. Intracranial administration of nimodipine formulations may produce higher concentration of nimodipine in the cerebrospinal fluid (CSF) than is possible to achieve orally or intravenously, while resulting in lower incidence of systemic hypotension. The aim of this study was to provide information on plasma and CSF levels of nimodipine in beagle dogs as a comparative data for development of experimental intracranial treatment modalities. Plasma levels of nimodipine were measured after current 30 and 60 mg single oral dose of nimodipine (Nimotop(®) 30 mg tablets), a single intravenous bolus 0.72 mg/dog of nimodipine (Nimotop(®) 0.2 mg/ml infusion solution) and CSF levels after 60 mg single oral dose of nimodipine. CSF/Plasma concentration ratio of nimodipine after oral administration of 60 mg at 1 h was 0.013 ± 0.0005. The mean terminal elimination half-life of nimodipine after i.v. bolus dose 0.72 mg was 1.8 h and mean plasma clearance was 40.3 and 3.4 l/h/kg. Absolute bioavailability was 22 %. Maximum plasma concentration and area under the plasma concentration-time curve from time of administration until the last measurable plasma concentration increased in a dose-proportional manner comparing the exposure parameters at oral doses of 30 and 60 mg. Individual variation in the kinetic profile of nimodipine was measured.
authors: Faculty of Medicine, University of Turku, Kiinamyllynkatu 4-8, P.O. Box 52, 20520, Turku, Finland.|Department of Neurosurgery, Helsinki University Central Hospital, Topeliuksenkatu 5, P.O. Box 266, 00029, Helsinki, Finland.
authors: Janne
authors: J
authors: Koskimäki
authors: Turku PET Centre, University of Turku and Turku University Hospital, Kiinamyllynkatu 4-8, P.O Box 52, 20521, Turku, Finland.
authors: Miikka
authors: M
authors: Tarkia
authors: Chemistry and Safety Sciences, R&D, Orion Corporation, Orion Pharma, Orionintie 1A, P.O. Box 65, 02101, Espoo, Finland.
authors: Tuula
authors: T
authors: Ahtola-Sätilä
authors: Chemistry and Safety Sciences, R&D, Orion Corporation, Orion Pharma, Orionintie 1A, P.O. Box 65, 02101, Espoo, Finland.
authors: Lasse
authors: L
authors: Saloranta
authors: Department of Neurosurgery, Helsinki University Central Hospital, Topeliuksenkatu 5, P.O. Box 266, 00029, Helsinki, Finland.
authors: Aki
authors: A
authors: Laakso
authors: Clinical Neurosciences, Department of Neurosurgery, Turku University Central Hospital, Hämeentie 11, P.O. Box 52, 20521, Turku, Finland. janek.frantzen@tyks.fi.
authors: Janek
authors: J
authors: Frantzén
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid; D002555:Cerebrospinal Fluid / Q000378:metabolism*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004285:Dogs; D006207:Half-Life; D006801:Humans; D009553:Nimodipine / Q000008:administration & dosage* / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D013607:Tablets / Q000008:administration & dosage / Q000378:metabolism
chemical_list: D002121:Calcium Channel Blockers; D013607:Tablets; D009553:Nimodipine
keywords: Cerebrospinal fluid; Delayed cerebral ischemia; Dog; Nimodipine; Pharmacokinetic; Subarachnoid hemorrhage; Vasospasm
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