IN-VITRO AND IN-VIVO TRANSPORT OF ZIDOVUDINE (AZT) ACROSS THE BLOOD-BRAIN-BARRIER AND THE EFFECT OF TRANSPORT INHIBITORS

The transport of the antiviral nucleoside analogue zidovudine (3'-azid o-3'-deoxythymidine; AZT) into the central nervous system (CNS) was ch aracterized in vitro and in vivo. The in vitro model consisted of prim ary cultures of isolated bovine capillary endothelial cells. The trans port rate of AZT across the monolayer, expressed as endothelial permea bility P, was determined following luminal and abluminal administratio n. P did not differ between the two administration sites (luminal, 1.6 5 +/- 0.44 cm/min/10(3); abluminal, 1.63 +/- 0.28 cm/min/10(3)). The t ransport of AZT across the endothelial cell monolayer was found to be concentration independent in the range between 0.4 and 50 mu g/mL. AZT transport was not affected by pretreatment of the cells with either m etabolic inhibitors (DODG and DODG/NaN3) or probenecid. This suggests that AZT passes the monolayer mainly by passive diffusion. The in vivo transport of AZT across the blood-brain barrier and the blood-CSF bar rier was studied in male Wistar rats after coadministration of potenti al inhibitors of active transport of AZT: probenecid (organic anion tr ansport) and thymidine (nucleoside transport). Intracerebroventricular and intravenous coadministration of probenecid caused a significant ( P < 0.001) increase in the CSF/plasma concentration ratio compared to the control phase, indicating that the organic anion carrier is involv ed in AZT transport from CSF to blood. Since there was no effect of pr obenecid on the transport of AZT in vitro, it is suggested that this c arrier is located at the choroid plexus. Coadministration of thymidine did not affect the CSF/plasma concentration ratio, suggesting that a nucleoside carrier system is not involved in AZT transport into or out of the CNS.