1991 Volume 39 Issue 11 Pages 1046-1051
We investigated the effect of probenecid on the pharmacokinetics of zidovudine (AZT) in beagle dogs and HIV-1 positive patients and obtained the following results.
1. In beagle dogs the maximum concentration (Cmax) and the area under the curve (AUC) of AZT increased with the co-administration of probenecid.In contrast, the Cmax and AUC of AZT's metabolite, glucuronide conjugated AZT (GAZT), decreased with the probenecid co-administration.
2. In HIV-1 positive patients the AUCs of both AZT and GAZT increased with probenecid coadministration. This increased AUC was more marked with GAZT
3. The urinary excretion of AZT and GAZT was also affected by this probenecid treatment. After probenecid administration, the urinary recovery rate of both AZT and GAZT decreased in beagle dogs, while in patients that of AZT increased sightly and GAZT decreased.
4. These results indicate that probenecid may inhibit the glucuronide conjugation of AZT in the liver and prevent the tubular secretion of AZT and especially GAZT in the kidney.
5. The concomitant use of probenecid doubled the duration of AZT levels above the lowest inhibitory concentration (0.3-0.5μg/ml) of HIV-1 replication in the patients.
The above results suggest that if the effect of AZT is related to the duration of the effective blood concentration, probenecid co-administration may enchance the inhibitory effect of AZT on HIV replication. The results also show the possibility of reducing the dose of AZT with co-administration of probenecid and thus a decrease in the adverse effects of AZT.
