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The effects of probenecid on the pharmacokinetics of 2',3'-dideoxyinosine (ddl) and on the distribution of ddl to cerebrospinal fluid (CSF) and brain tissue were determined in rats during and after a 2-hr i.v. infusion of ddl, 125 mg/kg/hr. Probenecid-treated rats received a loading dose of probenecid followed by an i.v. infusion of probenecid initiated 1 hr before and continued during and for 2 hr after termination of the ddl infusion. Plasma concentrations of probenecid averaged 221 +/- 34 micrograms/ml upon termination of the ddl infusion and 258 +/- 34 micrograms/ml (mean +/- S.D., n = 4) 1 hr later. In the probenecid-treated animals, ddl concentrations were higher in plasma (1.5-fold), brain (1.5-fold) and CSF (5.4-fold) at the termination of the ddl infusion and postinfusion concentrations declined more slowly compared to controls. Postinfusion, the CSF/plasma and brain/plasma ratios steadily increased to a greater extent in the probenecid-treated rats compared to control animals. The time course of plasma, CSF and brain tissue concentrations were analyzed by nonlinear least-squares regression using two different compartmental models, one which neglected the direct exchange of drug between the CSF and brain parenchyma, whereas the other allowed for such exchange to occur and neglected direct vascular transfer of drug to brain tissue. Allowing exchange between the CSF and brain tissue gave slightly improved fitting of the data from both probenecid-treated and control rats.(ABSTRACT TRUNCATED AT 250 WORDS)
R E Galinsky, and
K K Flaharty, and
B L Hoesterey, and
B D Anderson
April 1990,
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