THE EFFECTS OF INDOMETHACIN AND NAPROXEN ON ZIDOVUDINE PHARMACOKINETICS

The effects of indomethacin and naproxen on zidovudine (ZDV) pharmacokinetics were studied in six patients with the acquired immunodeficiency syndrome (AIDS), AIDS related complex (ARC) or asymptomatic HIV disease using a placebo-controlled cross-over design. Indomethacin 25 mg twice daily or naproxen 250 mg twice daily did not alter ZDV pharmacokinetics compared with placebo. The mean AUC value for the glucuronidated metabolite, GZDV, was reduced from 26.6 +/- 11.7 mumol l-1 h in the presence of placebo to 20.9 +/- 8.3 mumol l-1 h (95% C.I. of the difference 1.39-9.98; P < 0.05) following treatment with naproxen 250 mg twice daily for 3 days. The small decrease in plasma GZDV in the naproxen phase reflects an increase in clearance of ZDV to other metabolites and/or a decrease in the formation clearance to GZDV and/or an increase in the clearance of GZDV. A decrease in formation clearance to GZDV would be consistent with the results of in vitro studies reported previously. No significant increase in ZDV concentration in the presence of naproxen may reflect a lower sensitivity of parent drug measurements to selective inhibition of parallel pathways of metabolism. The clinical significance of these findings is unknown but toxicity may be increased if a decreased formation of GZDV is accompanied by shunting of metabolism to 3'-amino-3'-deoxythymidine which is alleged to be cytotoxic.