title: Pharmacokinetics of the active metabolites of ethyl loflazepate in elderly patients who died of asphyxia associated with benzodiazepine-related toxicity.
abstract: We determined the pharmacokinetics of ethyl loflazepate (Lof) in elderly patients who died of benzodiazepine-related toxicity. Three elderly patients with body mass indexes of less than 17 kg/m2 died of asphyxia after having taken maintenance doses of Lof for 2 to 3 weeks. We measured serum concentrations of the active metabolites of Lof using gas chromatography-mass spectrometry and a benzodiazepine receptor assay to determine the pharmacokinetics of each. On admission, the serum concentrations of the active metabolites of Lof ([Lofl) were 256 ng/mL, 425 ng/mL, and 177 ng/mL in cases 1, 2, and 3, respectively. Serum benzodiazepine-receptor binding activities, expressed as diazepam equivalent concentrations ([Bz]), were 1800 ng/mL, 2200 ng/mL, and 1500 ng/mL. The T1/2(beta) of [Lof] were 124 and 121 h in cases 1 and 2 and the T1/2(beta) of [Bz] were 75 and 87 h. The distribution volume in the elderly was reduced due to a small lipid compartment, and total drug clearance was decreased due to the decline in liver and kidney function. These changes did not prolong T1/2(beta) but did increase plasma concentrations of active metabolites, especially in case 2, and a slight decrease in protein binding increased the amount of free active metabolites greatly.
authors.affiliation: Department of Emergency and Critical Care Medicine, Kitasato University, School of Medicine, 1-15-1 Kitasato, Sagamihara Kanagawa 228-8555, Japan. yk119@kitasato-u.ac.jp
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Kamijo
authors.forename: Izumi
authors.initials: I
authors.lastname: Hayashi
authors.forename: Takashi
authors.initials: T
authors.lastname: Nishikawa
authors.forename: Kuniko
authors.initials: K
authors.lastname: Yoshimura
authors.forename: Kazui
authors.initials: K
authors.lastname: Soma
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000402:Airway Obstruction / Q000139:chemically induced* / Q000401:mortality; D001569:Benzodiazepines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000506:poisoning*; D015992:Body Mass Index; D003643:Death; D005260:Female; D058785:GABA-A Receptor Agonists; D008401:Gas Chromatography-Mass Spectrometry; D006207:Half-Life; D006801:Humans; D008297:Male; D011963:Receptors, GABA-A / Q000097:blood
chemical_list: D058785:GABA-A Receptor Agonists; D011963:Receptors, GABA-A; D001569:Benzodiazepines; C029617:ethyl loflazepate