The effect of a therapeutic dose of fluconazole on the disposition of zidovudine was evaluated in 12 men infected with human immunodeficiency virus. The study was designed as a randomized, two-period, two-treatment, crossover trial. On two occasions, 21 days apart, patients received either zidovudine alone or zidovudine (each, 200 mg every 8 h) and fluconazole (400 mg daily) for 7 days. Fluconazole coadministration decreased (P < .001) the apparent oral serum clearance of zidovudine by 43% and the apparent oral formation clearance to zidovudine glucuronide (GZDV) by 48%, resulting in increases (P < .002) in the area under the serum concentration time curve (74%), the maximum serum concentration (84%), and the terminal half-life (128%) of zidovudine. The molar ratio of GZDV to zidovudine recovered in urine was reduced by 34% with fluconazole (P < .001). These pharmacokinetic changes suggest that 400 mg of fluconazole inhibited the conversion of zidovudine to GZDV. Patients receiving this combination should be monitored for the development of zidovudine-related adverse reactions.

3Western Region, Health Protection Branch, Health Canada, Vancouver, British Columbia, Canada Aims The objective of the study was to determine the effect of multiple doses of rifampicin on the steady-state pharmacokinetics of zidovudine and its 5∞-glucuronosyl (GZDV) and 3∞-amino (AMT) metabolites. Methods Eight asymptomatic HIV-infected patients (seven male, one female) participated in this three-period longitudinal study. Each patient received zidovudine (200 mg every 8 h) for 14 days ( period 1), followed by rifampicin (600 mg every 24 h) with zidovudine for 14 days ( period 2), and then zidovudine alone for a further 14 days ( period 3). Blood and urine samples were collected over 6 h on the last day of each period for measurements of zidovudine and GZDV by h.p.l.c.-u.v. and AMT by h.p.l.c.-m.s-m.s. Results Compared with zidovudine-alone values in period 1, 14 days of coadministration with rifampicin significantly increased zidovudine oral clearance (89%) and formation clearances to GZDV (100%) and AMT (82%). Correspondingly, there were decreases in maximum plasma concentration (43%), AUC (47%) and urine recovery (37%) of zidovudine. GZDV/zidovudine and AMT/zidovudine AUC ratios increased by 99% and 36%, respectively, despite a significant 29% decrease in AMT AUC. After stopping rifampicin for 14 days, values of these pharmacokinetic parameters returned to within 26% of baseline. Over the three periods AMT plasma levels were <18 ng ml −1 (n=6) and <40 ng ml −1 (n=2), and molar AMT/zidovudine AUC ratios ranged from 1.7% to 4.5%. Conclusions Rifampicin induced zidovudine glucuronidation and amination pathways resulting in decreased plasma and urine exposures to zidovudine. AMT plasma exposure decreased because induction was more pronounced for the major GZDV metabolite. The magnitude of the residual inductive effect was minimal at 14 days after stopping rifampicin. inhibitors and non-nucleoside reverse transcriptase

No abstract

Male Swiss Webster mice, treated with N-acetylcysteine (NAC, 500 mg/kg po) 1 h following acetaminophen (NAPA, 350 mg/kg po) administration, had control levels of transaminases indicating that NAC protects against NAPA-induced hepatotoxicity by postabsorption antidotal mechanism(s). Hepatic congestion induced by NAPA was reduced by NAC. Significantly higher elimination rate constants (K) for indocyanine green (500 micrograms/kg, iv) in mice treated with NAPA and NAC (K = 0.676 +/- 0.062) than in animals receiving NAPA alone (0.341 +/- 0.105) suggested NAC improved or preserved the hepatic circulation of the compromised liver. This NAC-induced improvement and (or) preservation of hepatic circulation was reflected in biliary and urinary excretion of acetaminophen and its metabolites by a general increase in elimination during the first 6 h (70.2 +/- 2.6 vs. 32.6 +/- 7.1%), and in the repletion of glutathione (GSH) in the liver by a return to control levels more quickly (3 vs. greater than 5 h) following depletion by NAPA. The metabolic consequences of the postabsorption antidotal effect of NAC in the compromised liver was a preferential excretion of sulphydryl-derived metabolites in the 1-4 h bile (GSH conjugate 11.30 +/- 1.25 vs. 7.25 +/- 0.39%) which was subsequently observed in the urine by preferential excretion of glutathione degradation products.

Therapeutic doses of naproxen do not significantly affect the pharmacokinetic disposition of zidovudine.