THE EFFECTS OF INDOMETHACIN AND NAPROXEN ON ZIDOVUDINE PHARMACOKINETICS

The effects of indomethacin and naproxen on zidovudine (ZDV) pharmacok inetics were studied in six patients with the acquired immunodeficienc y syndrome (AIDS), AIDS related complex (ARC) or asymptomatic HIV dise ase using a placebo-controlled cross-over design. Indomethacin 25 mg t wice daily or naproxen 250 mg twice daily did not alter ZDV pharmacoki netics compared with placebo. The mean AUC value for the glucuronidate d 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 diffe rence 1.39-9.98; P < 0.05) following treatment with naproxen 250 mg tw ice daily for 3 days. The small decrease in plasma GZDV in the naproxe n phase reflects an increase in clearance of ZDV to other metabolites and/or a decrease in the formation clearance to GZDV and/or an increas e in the clearance of GZDV. A decrease in formation clearance to GZDV would be consistent with the results of in vitro studies reported prev iously. No significant increase in ZDV concentration in the presence o f naproxen may reflect a lower sensitivity of parent drug measurements to selective inhibition of parallel pathways of metabolism. The clini cal significance of these findings is unknown but toxicity may be incr eased if a decreased formation of GZDV is accompanied by shunting of m etabolism to 3'-amino-3'-deoxythymidine which is alleged to be cytotox ic.