Competitive inhibition of zidovudine clearance by probenecid during continuous coadministration.
The pharmacokinetics of zidovudine in the rabbit were studied during coadministration of probenecid at two infusion rates. Each animal (n = 6) served as its own control during an initial 8-hr infusion of zidovudine. In the second 8-hr infusion period, probenecid was coadministered with zidovudine. Urine samples were collected by bladder flush hourly for 19 hr. Plasma samples were taken at the midpoint of the urine collection interval and at predetermined intervals for 3 hr postinfusion. Plasma concentrations of zidovudine reached steady state during control periods but showed incomplete attainment of steady state during the infusions of probenecid at the higher rate. Total and renal clearance of zidovudine were reduced by 24.0 +/- 4.0 and 20.7 +/- 15%, respectively, during low-dose probenecid treatment and 48.9 +/- 7.4 and 55.7 +/- 3.4%, respectively, with high-dose probenecid treatment. Plasma probenecid concentrations during low-dose and high-dose infusion were 56.9 +/- 12 and 248 +/- 42 micrograms/ml. Postinfusion data showed that the zidovudine terminal half-life during high-dose probenecid treatment was longer than that with low-dose probenecid treatment (58.2 +/- 4.6 vs 39.0 +/- 9.1 min). The volume of distribution of zidovudine also decreased (1.76 +/- 0.27 vs. 1.10 +/- 0.095 L/kg) as a result of probenecid coadministration. The results are consistent with competitive inhibition of renal and nonrenal clearances. A drug interaction model relating zidovudine clearances to plasma probenecid concentrations was derived. Michaelis-type constants for probenecid inhibition of zidovudine renal and nonrenal clearances were 73 and 55 micrograms/ml, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Wong
S L
SL
Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis 55455.
Hedaya
M A
MA
Sawchuk
R J
RJ
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004347:Drug Interactions; D007262:Infusions, Intravenous; D008297:Male; D008954:Models, Biological; D011339:Probenecid / Q000494:pharmacology*; D011817:Rabbits; D015215:Zidovudine / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics*
D015215:Zidovudine; D011339:Probenecid