No abstract

Cynomolgus monkeys had microdialysis probes implanted under ketamine anesthesia into peripheral veins, thigh muscles, and the brain in order to sample the extracellular fluid for the concentrations of unbound nucleoside analogs. A dose of 25 mg of zidovudine or 3'-fluoro-3'-deoxythymidine (FLT) per kg was administered subcutaneously to each of three animals. Relatively high antiviral concentrations of FLT Microdialysis. Anesthesia was induced by and maintained with ketamine given intravenously. The monkeys were placed in a stereotaxic instrument. In each monkey two microdialysis probes (CMA/10; CMA Microdialysis AB, Stockholm, Sweden) with a diffusible area of 10.0 by 0.5 mm (length by outer diameter) were implanted bilaterally into the striatum through a guide cannula which was secured to the skull bone by means of an acrylic dental cement. Two microdialysis probes were also implanted in muscle tissue in the thigh, and two probes were implanted into a dorsal superficial vein of the lower limb. Duplicate probes were used to prevent loss of data. Dialysates were collected in 20-min fractions and covered with tube caps. After implantation, each microdialysis probe was perfused for 60 min with degassed Ringer solution (ACO, Stockholm, Sweden) at a constant flow rate of 2.0 pl/min. Next, to determine the recovery over the dialysis membrane in vivo, each probe was perfused with a 10 ,uM solution of zidovudine or FLT at the same rate for 60 min and then the perfusion medium was switched back to Ringer solution for a washout period. The loss of drug to the tissue by diffusion over the dialysis membrane was measured as the difference between the drug concentration in the perfusion medium (10 ,uM) and the drug concentration in the dialysate. The proportion of drug lost over the dialysis membrane was used as an estimate of the in vivo recovery (18). After the washout period of 60 min,