Zidovudine, diclofenac and ketoprofen pharmacokinetic interactions in rats

Zidovudine (AZT) is widely used for the management of human immunodeficiency virus (HIV) infections. Non-steroidal anti-inflammatory drugs (NSAIDs) are often used for relief of non-specific fever and musculoskeletal pain in patients with HIV including those with AZT-induced myopathy. The effects of single oral doses of diclofenac and ketoprofen on AZT pharmacokinetics were studied in rats. The influence of AZT on the pharmacokinetics of diclofenac or ketoprofen was also investigated. The administration of diclofenac (3 mgkg(-1)) or ketoprofen (1 mgkg(-1)) did not significantly alter AZT (1.5 mgkg(-1)) pharmacokinetic parameters compared with administering AZT alone. There was no significant difference between the pharmacokinetics of ketoprofen given alone or in combination with AZT. However, the co-administration of AZT with diclofenac affected the pharmacokinetics of diclofenac. The Cmax of diclofenac was significantly (P < 0.05) increased by approximately threefold within a shorter time (0.6+/-0.2 h). The mean AUC value for diclofenac was increased from 2.29 to 5.04 microg mL(-1) h in the presence of AZT. AZT decreased the mean apparent clearance of diclofenac by 54%. The increase in diclofenac concentrations could be attributed to a decrease in its clearance or delay in its metabolite formation due to a competitive effect. The results show that diclofenac and AZT should be given with caution because of the possible increase of diclofenac toxicity, in anticipation of follow-up clinical studies to examine this finding in man. AZT and ketoprofen could be a safe combination since no pharmacokinetic interaction was detected.