Differences in the brain penetration of the anticholinergic drugs trospium chloride and oxybutynin

Abstract

Introduction: This study was performed to compare tissue distribution and brain penetration of the anticholinergic drugs trospium chloride and oxybutynin in a mouse model. Additionally, the role of the drug efflux carrier P-glycoprotein for hepatobiliary and urinary excretion and the blood-brain barrier permeability of oxybutynin were evaluated by using knockout mice that were deficient in P-glycoprotein. Methods: Radio-labeled trospium chloride and oxybutynin were administered orally (1 mg/kg) to wild-type and P-glycoprotein deficient knockout mice. Tissue distribution of the drugs was analyzed after 12 hours. Additionally, oxybutynin was applied intravenously to gall bladder cannulated mice of both types. Drug excretion into bile and urine was analyzed over 2 hours by catheterization. RESULTS: Absolute drug concentrations in the brain were almost 200-fold higher for oxybutynin (~200 ng/g) compared with trospium chloride (~1 ng/g) when applied at an equal dosage of 1 mg/kg orally, whereas concentrations in the liver were only 15-fold different (~300 ng/g for oxybutynin and ~20 ng/g for trospium chloride). P-glycoprotein deficient knockout mice after oxybutynin application showed no significant differences in brain penetration or drug excretion into bile and urine when compared with wild-type mice. CONCLUSION: Brain penetration of oxybutynin highly exceeds that of trospium chloride at an equal dosage (1 mg/kg, given orally). In contrast to trospium chloride, brain penetration of oxybutynin is not restricted by the drug efflux carrier P-glycoprotein because oxybutynin is not a P-glycoprotein substrate in vivo. © 2010 UroToday International Journal.