A. Green, T. K. Murray, A. Misra
Jan 1, 2000
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Journal
British Journal of Pharmacology
Abstract
A single dose of clomethiazole (600 μmol kg−1 i.p.) has previously been shown to be neuroprotective in the gerbil model of global ischaemia. In gerbils, clomethiazole (600 μmol kg−1) injection produced a rapid appearance (peak within 5 min) of drug in plasma and brain and similar clearance (plasma t1/2: 40 min) from both tissues. The peak brain concentration (226±56 nmol g−1) was 40% higher than plasma. One major metabolite, 5‐(1‐hydroxyethyl‐2‐chloro)‐4‐methylthiazole (NLA‐715) and two minor metabolites 5‐(1‐hydroxyethyl)‐4‐methylthiazole (NLA‐272) and 5‐acetyl‐4‐methylthiazole (NLA‐511) were detected in plasma and brain. Evidence suggested that clomethiazole is metabolized directly to both NLA‐715 and NLA‐272. Injection of NLA‐715, NLA‐272 or NLA‐511 (each at 600 μmol kg−1) produced brain concentrations respectively 2.2, 38 and 92 times greater than seen after clomethiazole (600 μmol kg−1). Clomethiazole (600 μmol kg−1) injected 60 min after a 5 min bilateral carotid artery occlusion in gerbils attenuated the ischaemia‐induced degeneration of the hippocampus by approximately 70%. The metabolites were not neuroprotective at this dose. In mice, clomethiazole (600 μmol kg−1) produced peak plasma and brain concentrations approximately 100% higher than in gerbils, drug concentrations in several brain regions were similar but 35% higher than plasma. Clomethiazole (ED50: 180 μmol kg−1) and NLA‐715 (ED50: 240 μmol kg−1) inhibited spontaneous locomotor activity. The other metabolites were not sedative (ED50 >600 μmol kg−1). These data suggest that the neuroprotective action of clomethiazole results from an action of the parent compound and that NLA‐715 contributes to the sedative activity of the drug.