No abstract

Ticlopidine, a new antithrombotic agent, and theophylline, a widely used bronchodilator drug, are both almost completely metabolized in the liver. To evaluate an interaction between these two drugs, we studied theophylline pharmacokinetics before, after 10 days of ticlopidine administration, and 1 month later in 10 healthy volunteers. We found a highly significant increase in the theophylline elimination half-life (P less than 0.001) and a comparable reduction in its total plasma clearance (P less than 0.001) after ticlopidine treatment. Pharmacokinetic parameters returned to initial values within 30 days after ticlopidine withdrawal. Moreover, no changes in theophylline pharmacokinetic parameters were observed 3 months later, before and after 10 days of placebo administration. Our results seem to exclude direct liver toxicity and may suggest a reversible inhibition of the liver metabolic capacity of theophylline.

The plasma clearance after oral administration of a completely absorbed drug that is metabolized by the liver depends on its intrinsic clearance. In cirrhosis the bioavailability of a flow-dependent drug increases because of both portosystemic shunting and hepatocyte dysfunction. A drug with a high extraction ratio, lidocaine, and a drug with a low extraction ratio, theophylline, were administered to 27 patients with cirrhosis and 16 control subjects. We found a significant impairment of both theophylline clearance (p less than 0.001) and lidocaine clearance (p less than 0.001) and an increase in the lidocaine peak concentration (p less than 0.001). The three parameters were significantly correlated with each other. The impairment of theophylline metabolism did not correlate with other indexes of disease severity, whereas lidocaine clearance was lower and lidocaine peak level higher in patients with decompensated cirrhosis and evidence of portal hypertension. Thus impairment in lidocaine disposition, which reflects both hepatocyte dysfunction and portosystemic shunting, correlated closer with the severity of liver disease than did theophylline metabolism.

No abstract

No abstract