Probenecid inhibits the metabolic and renal clearances of zidovudine (AZT) in human volunteers.
The effect of probenecid on the disposition of AZT was investigated in a pilot study in two healthy volunteers. The pharmacokinetics of AZT were examined after a single oral dose of 200 mg with and without probenecid coadministration in a balanced crossover study. Administration of 500 mg probenecid every 6 hr prior to and during AZT dosing resulted in an increase in the average AUCAZT from 89 micrograms.min/ml (control) to 191 micrograms.min/ml during probenecid treatment. This was manifested by a corresponding decrease in CLTOT/F, which is attributed to the inhibitory effect of probenecid on the glucuronidation and renal excretion of AZT. Average CLR and CLTOT/F of AZT decreased from 4.76 and 28.7 to 2.98 and 14.1 ml/min/kg during control and probenecid treatment, respectively. AZT glucuronidation was affected to a greater extent than its renal excretion, as reflected by the decreased ratio of GAZT/AZT urinary recoveries. The terminal half-life of AZT was slightly longer during probenecid administration. That only a small change in the half-life occurred indicates that probenecid also reduced the volume of distribution of AZT. The CLR of GAZT decreased from an average of 11.3 ml/min/kg (control) to 2.63 ml/min/kg during probenecid treatment, resulting in a greater than 3.5-fold increase in AUCGAZT. Probenecid did not affect the blood/plasma distribution or the plasma protein binding of AZT. These preliminary findings suggest that it may be possible to maintain effective plasma AZT concentrations in AIDS patients receiving a reduced daily dose, in combination with probenecid.
Hedaya
M A
MA
Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis 55455.
Elmquist
W F
WF
Sawchuk
R J
RJ
D000328:Adult; D001798:Blood Proteins / Q000378:metabolism; D004347:Drug Interactions; D005965:Glucuronates / Q000097:blood / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D011339:Probenecid / Q000494:pharmacology*; D011485:Protein Binding; D015215:Zidovudine / Q000493:pharmacokinetics* / Q000652:urine
D001798:Blood Proteins; D005965:Glucuronates; D015215:Zidovudine; D011339:Probenecid