Chen C L, Sangiah S, Roder J D, Chen H, Berlin K D, Garrison G L, Scherlag B J, Lazzara R
Department of Physiological Sciences, Oklahoma State University, Stillwater, USA.
Arzneimittelforschung. 1995 Jun;45(6):670-5.
GLG-V-13 (3-[4-(1H-imidazol-1-yl)benzoyl]-7-isopropyl-3,7-diazabicyclo [3.3.1] nonane dihydroperchlorate, CAS 155029-33-7) has been shown to be a potent class III antiarrhythmic agent. The oral and intravenous pharmacokinetics and plasma protein binding of GLG-V-13 in dogs and in rabbits have now been investigated. Plasma GLG-V-13 concentration-time profiles, following an i.v. bolus dose of 6 mg/kg, were fitted to a 2-compartment model. The volume of distribution at steady state (Vd(ss)), the total systemic (ClB), and the elimination half-life (t1/2 beta) were 4.441 l/kg, 1.113 l/h/kg, and 2.485 h in dogs and 3.723 l/kg, 1.548 l/h/kg, and 1.401 h in rabbits. Following i.v. dosing, approximately 9.38% of the parent compound was excreted in dogs urine (0-72 h). Changes in plasma GLG-V-13 concentrations, after oral administration of GLG-V-13 (6 mg/kg), were best described by the 1-compartment pharmacokinetic model. The tmax and Cmax were 1.69 h, 0.54 mg/l in dogs and 1.44 h, 0.35 mg/l in rabbits. On oral administration, GLG-V-13 was moderately eliminated (t1/2kel' 1.867 h-1 in dogs and 3.961 h-1 in rabbits, respectively). Oral bioavailability was estimated to be 53.2% +/- 11.3% in dogs and 66.7% +/- 7.7% in rabbits. About 8.74% of the oral dose (6 mg/kg) was excreted via the dog urine (0-72 h). In vitro binding of GLG-V-13 to dog plasma protein was 29.4 +/- 9.90% (from 0.5 to 4 mg/l). Ex vivo binding of GLG-V-13 to dog plasma protein was 10.4 +/- 7.20%.(ABSTRACT TRUNCATED AT 250 WORDS)
GLG-V-13（3-[4-(1H-咪唑-1-基)苯甲酰基]-7-异丙基-3,7-二氮杂双环[3.3.1]壬烷二氢高氯酸盐，CAS 155029-33-7）已被证明是一种有效的III类抗心律失常药物。现已研究了GLG-V-13在犬和兔体内的口服及静脉药代动力学以及血浆蛋白结合情况。静脉注射6 mg/kg大剂量后，血浆GLG-V-13浓度-时间曲线符合二室模型。犬的稳态分布容积（Vd(ss)）、总全身清除率（ClB）和消除半衰期（t1/2β）分别为4.441 l/kg、1.113 l/h/kg和2.485 h，兔分别为3.723 l/kg、1.548 l/h/kg和1.401 h。静脉给药后，约9.38%的母体化合物经犬尿液排出（0至72小时）。口服GLG-V-13（6 mg/kg）后，血浆GLG-V-13浓度变化最适合用单室药代动力学模型描述。犬的tmax和Cmax分别为1.69小时、0.54 mg/l，兔分别为1.44小时、0.35 mg/l。口服给药后，GLG-V-13清除适度（犬的t1/2kel为1.867 h-1，兔为3.961 h-1）。犬的口服生物利用度估计为53.2%±11.3%，兔为66.7%±7.7%。约8.74%的口服剂量（6 mg/kg）经犬尿液排出（0至72小时）。GLG-V-13与犬血浆蛋白的体外结合率为29.4%±9.90%（浓度范围为0.5至4 mg/l）。GLG-V-13与犬血浆蛋白的体内结合率为10.4%±7.20%。（摘要截断于250字）
