PHARMACOKINETICS AND URINARY-EXCRETION OF DMXBA (GTS-21), A COMPOUND ENHANCING COGNITION

DMXBA (3-(2,4-dimethoxybenzylidene)-anabaseine, also known as GTS-21) is currently being tested as a possible pharmacological treatment of c ognitive 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 determine d by HPLC. Following a 5 mg kg(-1) iv dose, DMXBA plasma concentration declined bi-exponentially with mean (+/-SE) absorption and eliminatio n half-lives of 0.71 +/- 0.28 and 3.71 +/- 1.12 h, respectively. The a pparent steady state volume of distribution was 2150 +/- 433 mL kg(-1) , total body clearance was 1480 +/- 273 mL h(-1) kg(-1), and AUC(0-inf inity), was 3790 +/- 630 ng h mL(-1). Orally administered DMXBA was ra pidly absorbed. After oral administration of 10 mg kg(-1), a peak plas ma concentration of 1010 +/- 212 ng mL(-1) was observed at 10 min afte r dosing. Elimination half-life was 1.740 +/- 0.34 h, and AUC(0-infini ty), was 1440 +/- 358 ng h mL(-1). DMXBA peak brain concentration afte r oral administration was 664 +/- 103 ng g(-1) tissue, with an essenti ally 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 bioavailabili ty 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 +/- 0.0 3% of the total orally administered dose. Our data indicates that DMXB A oral bioavailability is primarily limited by hepatic metabolism. (C) 1998 John Wiley & Sons, Ltd.