Pharmacokinetics of guanabenz in patients with impaired liver function

The disposition of guanabenz, a centrally acting antihypertensive agent, was compared in 10 normotensive patients (eight males and two females) with chronic hepatic disease secondary to alcohol abuse and 10 healthy male volunteers after a 16 mg oral dose. Mean plasma concentrations of guanabenz were higher in patients with liver disease than in healthy subjects at every sampling time through 72 h after drug administration (p less than 0.05). In liver disease patients, the mean oral-dose clearance (2 L/h/kg) and terminal-phase volume of distribution (20 L/kg) were lower (p less than 0.001) than the respective values of 11 L/h/kg and 71 L/kg of healthy volunteers. The mean plasma half-life of patients with liver disease (6.4 h) was not significantly longer than that of healthy subjects (4.3 h). The mean fraction of unbound drug in the plasma was higher (p less than 0.01) in patients with liver disease (12.7%) than in healthy volunteers (10.5%). As guanabenz is eliminated predominantly via hepatic biotransformation and undergoes significant presystemic elimination after oral administration, the changes in guanabenz disposition in liver disease are not unexpected. They may be explained by enhanced oral bioavailability, owing to portosystemic shunting and/or reduced intrinsic clearance, combined with decreased hepatic clearance of guanabenz in liver disease. Individual dosage titration may be required when guanabenz is used for antihypertensive therapy of patients with chronic liver disease.