Determinants of pharmacologic effects and toxicity of benzodiazepine hypnotics: role of lipophilicity and plasma elimination rates.
A recent consensus statement from the American Psychiatric Association emphasized that plasma elimination half-life should not be confused with duration of action and labeled use of short half-life, high-potency benzodiazepines as a risk factor for chronic toxicity, cognitive impairment, true physiologic dependence, and discontinuance symptoms. Instead, other factors such as lipid solubility (lipophilicity), brain clearance rate, redistribution rate, receptor kinetics, and tolerance are currently thought to be additional important determinants of the pharmacodynamic profile of benzodiazepines. In in vitro experiments, quazepam and its first metabolite, 2-oxoquazepam, were found to have high lipophilicity, a finding that could have important clinical implications.
Arnold
J
J
Department of Pharmacology, University of Kansas, School of Medicine, Kansas City, MO.
D000818:Animals; D014151:Anti-Anxiety Agents; D001569:Benzodiazepines / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity; D001570:Benzodiazepinones / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D006993:Hypnotics and Sedatives / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity; D007700:Kinetics; D050356:Lipid Metabolism; D011963:Receptors, GABA-A / Q000378:metabolism; D012995:Solubility
D014151:Anti-Anxiety Agents; D001570:Benzodiazepinones; D006993:Hypnotics and Sedatives; D011963:Receptors, GABA-A; D001569:Benzodiazepines; C039103:2-oxoquazepam; C025130:quazepam