Mahnir V, Lin B, Prokai-Tatrai K, Kem W R
Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville 32610-0267, USA.
Biopharm Drug Dispos. 1998 Apr;19(3):147-51. doi: 10.1002/(sici)1099-081x(199804)19:3<147::aid-bdd77>3.0.co;2-9.
DMXBA (3-(2,4-dimethoxybenzylidene)-anabaseine, also known as GTS-21) is currently being tested as a possible pharmacological treatment of cognitive dysfunction in Alzheimer's disease. In this study, plasma and brain pharmacokinetics as well as urinary excretion of this compound have been evaluated in adult rats. DMXBA concentrations were determined by HPLC. Following a 5 mg kg-1 iv dose, DMXBA plasma concentration declined bi-exponentially with mean (+/- SE) absorption and elimination half-lives of 0.71 +/- 0.28 and 3.71 +/- 1.12 h, respectively. The apparent steady state volume of distribution was 2150 +/- 433 mL kg-1, total body clearance was 1480 +/- 273 mL h-1 kg-1, and AUC0-infinity was 3790 +/- 630 ng h mL-1. Orally administered DMXBA was rapidly absorbed. After oral administration of 10 mg kg-1, a peak plasma concentration of 1010 +/- 212 ng mL-1 was observed at 10 min after dosing. Elimination half-life was 1.740 +/- 0.34 h, and AUC0-infinity was 1440 +/- 358 ng h mL-1. DMXBA peak brain concentration after oral administration was 664 +/- 103 ng g-1 tissue, with an essentially constant brain-plasma concentration ratio of 2.61 +/- 0.34, which indicates that the drug readily passes across the blood-brain barrier. Serum protein binding was 80.3 +/- 1.1%. Apparent oral bioavailability was 19%. Renal clearance (21.8 mL h-1 kg-1) was less than 2% of the total clearance (1480 +/- 273 mL h-1 kg-1); urinary excretion of unchanged DMXBA over a 96 h period accounted for only 0.28 +/- 0.03% of the total orally administered dose. Our data indicates that DMXBA oral bioavailability is primarily limited by hepatic metabolism.
DMXBA（3-(2,4-二甲氧基亚苄基)-阿那abaseine，也称为GTS-21）目前正在作为阿尔茨海默病认知功能障碍的一种可能的药物治疗方法进行测试。在本研究中，已对成年大鼠体内该化合物的血浆和脑药代动力学以及尿排泄情况进行了评估。DMXBA浓度通过高效液相色谱法测定。静脉注射5mg/kg剂量后，DMXBA血浆浓度呈双指数下降，平均（±标准误）吸收半衰期和消除半衰期分别为0.71±0.28小时和3.71±1.12小时。表观稳态分布容积为2150±433mL/kg，全身清除率为1480±273mL/(h·kg)，AUC0-∞为3790±630ng·h/mL。口服DMXBA吸收迅速。口服10mg/kg后，给药后10分钟观察到血浆峰值浓度为1010±212ng/mL。消除半衰期为1.740±0.34小时，AUC0-∞为1440±358ng·h/mL。口服后DMXBA的脑峰值浓度为664±103ng/g组织，脑-血浆浓度比基本恒定为2.61±0.34，这表明该药物易于通过血脑屏障。血清蛋白结合率为80.3±1.1%。表观口服生物利用度为19%。肾清除率（21.8mL/(h·kg)）不到总清除率（1480±273mL/(h·kg)）的2%；96小时内未变化的DMXBA尿排泄量仅占口服总剂量的0.28±0.03%。我们的数据表明，DMXBA的口服生物利用度主要受肝脏代谢限制。
