Miller L G, Greenblatt D J, Abernethy D R, Friedman H, Luu M D, Paul S M, Shader R I
Division of Clinical Pharmacology, Tufts University School of Medicine, Boston, MA 02111.
Psychopharmacology (Berl). 1988;94(3):386-91. doi: 10.1007/BF00174694.
The benzodiazepine derivative flurazepam (FLZ) is widely used as a hypnotic, but the relative contributions of FLZ and its metabolites desalkylflurazepam (DA-FLZ), hydroxyethylflurazepam (ETOH-FLZ), and flurazepam aldehyde (CHO-FLZ) to overall clinical activity remain uncertain. A single 20 mg/kg dose of FLZ.HCl was administered to mice, with plasma and brain concentrations of FLZ and metabolites determined during 5 h after dosage. Brain and plasma concentrations of FLZ were maximal at 0.5 h after dosage, then declined rapidly in parallel, whereas those of DAFLZ were maximal at 2 h, then declined slowly. Concentrations of ETOH-FLZ, the most polar metabolite, were maximal at 0.5 h, and were undetectable after 3 h. Little CHO-FLZ was detected in either brain or plasma. A single 30-mg oral dose of FLZ.HCl was given to 18 human volunteers, with plasma levels determined over 9 days. FLZ was detected in plasma at low concentrations for no more than 3 h after dosage. ETOH-FLZ concentrations were higher and persisted for 8 h after dosage. CHO-FLZ reached intermediate peak levels and was present longer than FLZ or ETOH-FLZ. In contrast, DA-FLZ achieved the greatest peak concentrations, occurring at 10 h after dosage. Levels declined very slowly, with a mean half-life of 71.4 h, and were still detectable 9 days after FLZ dosage. Plasma free fractions (percent unbound) in mice were 40.3, 51.4, and 25.0% for FLZ, ETOH-FLZ and DA-FLZ, respectively; in humans, values were 17.2, 35.2, and 3.5%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
苯二氮䓬衍生物氟西泮（FLZ）被广泛用作催眠药，但FLZ及其代谢产物去烷基氟西泮（DA - FLZ）、羟乙基氟西泮（ETOH - FLZ）和氟西泮醛（CHO - FLZ）对总体临床活性的相对贡献仍不确定。给小鼠单次注射20 mg/kg剂量的盐酸氟西泮，在给药后5小时内测定血浆和脑内氟西泮及其代谢产物的浓度。氟西泮的脑和血浆浓度在给药后0.5小时达到峰值，然后迅速平行下降，而DA - FLZ的浓度在2小时达到峰值，然后缓慢下降。极性最强的代谢产物ETOH - FLZ的浓度在0.5小时达到峰值，3小时后无法检测到。在脑和血浆中均未检测到少量的CHO - FLZ。给18名人类志愿者单次口服30 mg剂量的盐酸氟西泮，在9天内测定血浆水平。给药后血浆中低浓度的氟西泮检测不超过3小时。ETOH - FLZ浓度较高，给药后持续8小时。CHO - FLZ达到中等峰值水平，存在时间比氟西泮或ETOH - FLZ更长。相比之下，DA - FLZ达到最大峰值浓度，出现在给药后10小时。水平下降非常缓慢，平均半衰期为71.4小时，在氟西泮给药9天后仍可检测到。小鼠体内血浆游离分数（未结合百分比）氟西泮、ETOH - FLZ和DA - FLZ分别为40.3%、51.4%和25.0%；在人类中，数值分别为17.2%、35.2%和3.5%。（摘要截断于250字）
