Time-Dependent Pharmacokinetic Interaction Between Zidovudine and Rifampicin Following Oral Administration of the Combination at 1000 and 2200 Hours

Rifampicin, an antitubercular agent, is a known metabolic inducer. Previous studies have suggested that rifampicin may interfere with the pharmacokinetics of oral zidovudine when the two drugs are co-administered. Circadian variations in the pharmacokinetics of rifampicin have been reported. We report here a circadian influence on the pharmacokinetics of zidovudine in the presence of rifampicin when administered orally in rabbits. Either zidovudine or zidovudine with rifampicin was administered orally at 10.00 or 22.00 h to 12 healthy rabbits in a randomized cross-over study. Serum zidovudine was estimated by HPLC. A significant (p <0.05) lowering of Cmax, (1/2), AUC(0-6h) and MRT was observed following zidovudine and rifampicin co-administration compared to zidovudine alone at 10.00 h. Accordingly clearance increased to a significant extent. However, such an interaction effect was masked following administration at 22.00 h. The time-dependent influence of rifampicin on the pharmacokinetics of zidovudine may be due to time-dependent changes in absorption and elimination of rifampicin, thus modifying its induction effect on the levels of UDP glucuronyl transferase and cytochrome P-450 content in liver which are responsible for metabolism of zidovudine.