The effect of diflunisal administration on the pharmacokinetics and metabolic fate of acetaminophen in man

Diflunisal is a fluorinated derivative of salicylic acid. It was synthesized with the intention of increasing potency, enhancing gastrointestinal tolerance and increasing duration of action over that of salicylate. Diflunisal is completely absorbed after oral administration and reaches peak plasma concentrations in two to three hours. It is highly bound to albumin, as is salicylate, with binding approaching 98-99%. Lin, et al observed a ten-fold increase in unbound diflunisal concentrations as total plasma concentratiojns ranges from 5 to 300 mcg.mL, demonstrating that diflunisal binding is concentrate-dependent. Diflunisal is extensively metabolized within the liver by UDP-glucuronosyltransferase to glucuronic acid conjugates; less than 5% of a dose is excreted unchanged in the urine. Diflunisal forms both an ether and ester glucuronide, which are excreted in the urine in nearly equal amounts. Acetaminophen is a widely used nonprescription analgesic and antipyretic which is also included in many combination prescription analgesic products. The rate of acetaminophen absorption is a function of the time required for gastric emptying. Peak plasma concentrations are reached within one hour of administration. Because both acetaminophen and diflunisal are metabolized to glucuronide conjugates, mutual inhibition of elimination may occur with concomitnat administration. The objectives of this investigation, were to: 1.) To describe the effect that diflunisal administration has on acetominophen pharmacokinetics in healthy volunteers and; 2.) To describe the mechanism9s0 responsible for this interaction if it were to occur.