caa a22 4500 477126421 CHVBK 20180405111651.0 cr unu---uuuuu 170330e19970701xx s 000 0 eng 10.1023/A:1012191515035 doi (NATIONALLICENCE)springer-10.1023/A:1012191515035 Microdialysis Studies of the Distribution of Stavudine into the Central Nervous System in the Freely-Moving Rat [Elektronische Daten] [Zheng Yang, Richard Brundage, Rashmi Barbhaiya, Ronald Sawchuk] Purpose. To study the extent and time course of distribution of stavudine (d4T) into the central nervous system (CNS) and to investigate the transport mechanisms of antiviral nucleosides in the CNS. Methods. Microdialysis with on-line HPLC analysis was used to measure drug concentrations in the brain extracellular fluid (ECF) and cerebrospinal fluid (CSF) in the freely-moving rat. The in vivo recovery of d4T and zidovudine (AZT) was estimated by retrodialysis, which was validated by the zero-net flux method. The CNS distribution of d4T was investigated during iv and intracerebroventricular (icv) infusion. In the subsequent studies, the effect of AZT on CNS distribution of d4T was examined. Results. During iv infusion, d4T distributed rapidly into the CNS. Its brain ECF/plasma and CSF/plasma steady-state concentration ratios were 0.33 ± 0.06 and 0.49 ± 0.12, respectively (n = 15). During icv infusion, the steady-state d4T concentrations in the brain ECF were 23-fold higher than those during iv infusion, whereas its steady-state plasma levels were about the same for these two routes. Coadministration of AZT with d4T did not alter their respective brain distribution and systemic clearance at the concentrations examined. More importantly, the steady-state brain ECF/plasma and CSF/plasma concentration ratios of d4T were about 2-fold higher than those of AZT (0.15 ± 0.04 and 0.25 ± 0.08) determined in the same animals. Conclusions. d4T readily crosses the blood-brain barrier (BBB) and blood-CSF barrier. An active efflux transport system in the BBB and blood-CSF barrier may be involved in transporting d4T out of the CNS. Direct icv administration of d4T can be used to enhance its brain delivery. Moreover, d4T exhibits a more favorable penetration into the CNS than AZT and therefore may be useful in the treatment of AIDS dementia complex. Plenum Publishing Corporation, 1997 stavudine nationallicence zidovudine nationallicence microdialysis nationallicence retrodialysis nationallicence central nervous system nationallicence brain uptake nationallicence blood-brain barrier nationallicence intracerebroventricular administration nationallicence AIDS nationallicence Yang Zheng Graduate Program in Pharmaceutics, College of Pharmacy, University of Minnesota, 55455, Minneapolis, Minnesota aut Brundage Richard Graduate Program in Pharmaceutics, College of Pharmacy, University of Minnesota, 55455, Minneapolis, Minnesota aut Barbhaiya Rashmi Pharmaceutical Research Institute, Dept. of Pharmacokinetics and Drug Metabolism, Bristol-Myers Squibb Co., P.O. Box 4000, 08543, Princeton, New Jersey aut Sawchuk Ronald Graduate Program in Pharmaceutics, College of Pharmacy, University of Minnesota, 55455, Minneapolis, Minnesota aut Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/7(1997-07-01), 865-872 0724-8741 14:7<865 1997 14 11095 https://doi.org/10.1023/A:1012191515035 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1023/A:1012191515035 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Yang Zheng Graduate Program in Pharmaceutics, College of Pharmacy, University of Minnesota, 55455, Minneapolis, Minnesota aut NATIONALLICENCE 700 1- Brundage Richard Graduate Program in Pharmaceutics, College of Pharmacy, University of Minnesota, 55455, Minneapolis, Minnesota aut NATIONALLICENCE 700 1- Barbhaiya Rashmi Pharmaceutical Research Institute, Dept. of Pharmacokinetics and Drug Metabolism, Bristol-Myers Squibb Co., P.O. Box 4000, 08543, Princeton, New Jersey aut NATIONALLICENCE 700 1- Sawchuk Ronald Graduate Program in Pharmaceutics, College of Pharmacy, University of Minnesota, 55455, Minneapolis, Minnesota aut NATIONALLICENCE 773 0- Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/7(1997-07-01), 865-872 0724-8741 14:7<865 1997 14 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer