Both phenolic and acyl glucuronidation pathways of diflunisal are impaired in liver cirrhosis

Abstract

The pharmacokinetics of diflunisal, a salicylate derivative that undergoes phenolic and acyl glucuronidation as well as sulphate conjugation, has been studied after a single oral dose (250 mg) in patients with cirrhosis (n = 5) and in healthy controls (n = 5). The plasma clearance of total (bound + unbound) diflunisal was 10.2 ml.min-1 in the control subjects and it was not affected by cirrhosis (10.9 ml.min-1). The plasma protein binding of diflunisal was significantly reduced in cirrhosis; the percentage of unbound diflunisal in plasma was 0.089 in the controls and 0.147 in the patients with cirrhosis. Plasma clearance of unbound diflunisal was significantly impaired in cirrhosis: 11.5 l.min-1 in control subjects vs 7.41.min-1 in cirrhotics. In cirrhotic patients, the unbound partial clearances to the phenolic and acyl glucuronides were both significantly reduced, by approximately 38%. The unbound partial clearance to the sulphate conjugate was not significantly affected by cirrhosis. The results show that both the phenolic and acyl glucuronidation pathways of diflunisal are equally susceptible to the effects of liver cirrhosis.