ZIDOVUDINE TRANSPORT WITHIN THE RABBIT BRAIN DURING INTRACEREBROVENTRICULAR ADMINISTRATION AND THE EFFECT OF PROBENECID

The elimination of zidovudine (AZT) from cerebrospinal fluid (CSF), it s distribution from CSF to brain tissue, and its transport from brain extracellular fluid (ECF) to plasma were studied during intracerebrove ntricular (icv) infusion in unanesthetized rabbits, The effect of prob enecid (PBD) on these transport processes was also studied. The concen tration of AZT in brain ECF was measured by microdialysis with retrodi alysis calibration for in viva recovery. Plasma and CSF were sampled a nd analyzed for AZT and PBD using HPLC. The elimination of ATT from CS F showed nonlinear characteristics as the icv infusion rate was increa sed to 1 mg/h kg. The estimated maximum transport capacity and dissoci ation constant were 3.5 mu g/min kg and 127 mu g/mL, respectively. The total linear elimination clearance from CSF was 0.0073 mL/min kg. The spatial distribution of AZT in brain during icv infusion was simulate d using a mathematical model which describes diffusive solute transpor t in brain ECF and efflux across the blood-brain barrier. This analysi s yielded a brain to plasma efflux rate constant of 0.040/min. This pa rameter and the elimination clearance from CSF decreased significantly by the end of an 8-hour period during which PBD was infused intraveno usly at a rate of 15 mg/h kg.