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Pharmacokinetics and extracellular distribution to blood, brain, and muscle of alovudine (3'-fluorothymidine) and zidovudine in the rat studied by microdialysis.

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Department of Pharmacology, Karolinska Institute, Stockholm, Sweden.


Microdialysis was applied to sample the free drug concentration in the extracellular fluid in brain, muscle, and blood of rats given alovudine (n = 6) (3'-fluorothymidine) or zidovudine (n = 5) (25 mg/kg s.c.). Alovudine and zidovudine were analyzed by means of high performance liquid chromatography (HPLC) with UV detection. The assay for zidovudine was validated by a radioimmunoassay. In addition, the plasma protein binding of the drugs was measured by microdialysis in vitro. The concentrations attained in blood and muscle were similar for each drug, with a Cmax of 57 microM (blood) and 54 microM (muscle) for alovudine and 38 and 46 microM, respectively, for zidovudine. In contrast the Cmax in brain was 8 microM for alovudine and 4 microM for zidovudine. The peak concentration was attained 20-40 min after injection in blood and muscle and 40-60 min after injection in the brain. The half-lives of zidovudine in both blood and muscle were 37 min and in brain 69 min. For alovudine the corresponding half-lives were significantly longer: 61, 58, and 105 min, respectively. The ratio of the AUC0-180 brain/blood was 0.257 for alovudine and 0.186 for zidovudine. The plasma protein binding of zidovudine was 10%, while alovudine was virtually unbound.

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