PHARMACOKINETIC INTERACTION BETWEEN ZIDOVUDINE AND VALPROIC ACID IN PATIENTS INFECTED WITH HUMAN-IMMUNODEFICIENCY-VIRUS

Zidovudine is metabolized to an inactive 5'-glucuronide and has a shor t plasma half-life requiring frequent dosing. The present study in six patients without symptoms who were infected with human immunodeficien cy virus was undertaken to determine if coadministration of valproic a cid which, like zidovudine, is metabolized by glucuronidation, would a lter zidovudine disposition. Under steady-state conditions for both dr ugs, the plasma area under the curve for zidovudine increased twofold with a corresponding decline in its oral clearance when given with val proic acid. The mean 5'-glucuronide/zidovudine urinary excretion ratio was reduced by more than 50%, and the amount of unconjugated zidovudi ne recovered in urine increased by more than twofold. There was no sig nificant increase in the plasma half-life of zidovudine. The effects o f valproic acid on zidovudine glucuronidation were related to plasma v alproic acid concentrations. Valproic acid inhibits glucuronidation of zidovudine and increases its oral bioavailability.