The metabolism of clomethiazole in gerbils and the neuroprotective and sedative activity of the metabolites.

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. British Journal of Pharmacology (2000) 129, 95–100; doi:10.1038/sj.bjp.0703042