Purpose: The purpose of this study was to determine the potential effect of probenecid on the pharmacokinetics of zalcitabine in HIV-positive patients.
Methods: Twelve patients received single oral 1.5 mg doses of zalcitabine alone and during probenecid treatment (500 mg at 8 and 2 hours before and 4 hours after zalcitabine dosing) in an open-label, randomized two-way crossover study with a one-week washout period between treatments. Serial blood and urine samples were collected over a 24 hour period and assayed for zalcitabine by a modified GC/MS method.
Results: Coadministration of probenecid with zalcitabine resulted in a decrease in mean (%CV) renal clearance of zalcitabine from 310 (28%) ml/min when zalcitabine was given alone to 180 (22%) ml/min with probenecid and a prolonged half-life from 1.7 hours to 2.5 hours. Mean AUCs increased from 59 ng.h/ml when zalcitabine was given alone to 91 ng.h/ml when given with probenecid. Considering the short half-life of zalcitabine (1-3 hours) relative to its dosing schedule, the pharmacokinetic changes observed in this study are not expected to result in significant accumulation during chronic dosing.
Conclusions: The results of this study show that co-administration of probenecid with zalcitabine results in a moderate decrease in renal clearance of zalcitabine due to inhibition of renal tubular secretion and a 50% increase in drug exposure. Although well tolerated in this single-dose study, patients taking this combination should be monitored closely for signs of toxicity and dosage reduction should be considered if warranted.