ZIDOVUDINE TRANSPORT IN THE RABBIT BRAIN DURING INTRAVENOUS AND INTRACEREBROVENTRICULAR INFUSION

The distribution of zidovudine (AZT) between plasma, brain extracellul ar fluid (ECF), and cerebrospinal fluid (CSF) was investigated in a cr ossover design study (n = 5) in unanesthetized rabbits. Drug was admin istered by intravenous (iv) and intracerebroventricular (icv) infusion s at the same infusion rate (1.5 mg/h . kg). The concentrations of AZT in ECF and CSF were measured by HPLC with microdialysis sampling. Pla sma concentrations of AZT were quantitated by HPLC. Following iv infus ion, the ECF- and CSF-to-plasma concentration ratios at steady state ( SS), were 0.19 +/- 0.05 and 0.29 +/- 0.06, respectively. These values were less than unity, indicating the existence of active transport pro cesses for the transport of ATT from brain to plasma across the blood- brain barrier (BBB) or blood-CSF barrier (BCB). The transport processe s were modeled by compartmental model analysis, and the results sugges t that the transport efficiency of ATT across the BBB is asymmetric; t hat is, the efflux clearance was five times greater than the influx cl earance. Similarly, the efflux clearance from CSF is three times large r than the influx clearance into CSF. The SS concentrations of AZT in brain ECF in the same animals that received an icy infusion of AZT in the crossover design study were approximately two orders of magnitude greater than those in animals following iv infusion at the same dosing rate. Nevertheless, the SS plasma concentrations of ATT were similar for both routes of administration (1.2 +/- 0.19 and 1.2 +/- 0.13 mu g/ mL for iv and icy routes, respectively), confirming that the brain is not an organ that exhibits first-pass metabolism under the present exp erimental conditions.