Pharmacokinetics and bioavailability of diclofenac in the rat

Diclofenac sodium is a widely used drug with interesting absorption and disposition features when administered to laboratory animals. The present study was undertaken to assess the pharmacokinetics of the drug after iv and gastrointestinal dosing to rats. Renal excretion of unchanged drug was negligible, but biliary excretion of the drug (unchanged and conjugated) was detected in bile duct-cannulated rats; it accounted for 27.2 and 31.2% of the total dose following iv and intraduodenal administration, respectively. Most of the drug excreted in the bile was conjugated diclofenac; unchanged drug accounted for only 4.7 and 5.4% of total diclofenac excreted in the bile after iv and intraduodenal dosing, respectively. In normal animals, intestinal absorption of the drug excreted in the bile resulted in higher drug concentrations in plasma than those obtained in bile duct-cannulated rats, but only after 60 min of dosing. When administered directly into the duodenum, diclofenac absorption was extremely fast and the maximum plasma diclofenac concentration was reached within 2 min. After oral dosing, an early peak was also observed, but it was lower than that obtained after intraduodenal dosing: 71% diclofenac bioavailability was found in bile duct-cannulated rats intraduodenally dosed, whereas in normal animals dosed by mouth a bioavailability of 79% was obtained. In normal animals intraduodenally dosed, an apparent bioavailability of 106% was observed. All of these features, particularly the influence of enterohepatic circulation on drug bioavailability, are discussed.