Pharmacokinetics of the active metabolites of ethyl loflazepate in elderly patients who died of asphyxia associated with benzodiazepine-related toxicity

We determined the pharmacokinetics of ethyl Ioflazepate (Lof) in elderly patients who died of benzodiazepine-related toxicity. Three elderly patients with body mass indexes of less than 17 kg/m 2 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 ([Lof]) 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 Tt/2(l~l of [Lof] were 124 and 121 h in cases 1 and 2 and the TtpII~ 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 Tt/2(I~ I but did increase plasma concentrations of active metabolites, especially in case 2,