Distributional transport kinetics of zidovudine between plasma and brain extracellular fluid/cerebrospinal fluid in the rabbit: investigation of the inhibitory effect of probenecid utilizing microdialysis.
The effect of probenecid (PBD) on the distributional transport of zidovudine (AZT) between plasma, cerebrospinal fluid (CSF) and brain extracellular fluid (ECF) was investigated by using microdialysis. New Zealand White rabbits received AZT, in a crossover design, during control and treatment periods. PBD was coadministered at one of two rates. One additional study involved a repeated control to investigate the possible existence of a period effect. In the low- and high-dose treatment groups, PBD decreased the total body clearance of AZT by 47.7 +/- 8.9 and 51.7 +/- 9.7%, respectively. PBD also decreased the clearance of AZT from CSF and thalamus ECF, prolonging the half-lives of AZT disappearance from the brain. Additionally, PBD elevated the AZT area under the concentration-time curve in the ventricular CSF 3- to 5-fold and the area under the thalamic ECF concentration-time curve by 5- to 6-fold, whereas the area under the plasma concentration-time curve increased only 2-fold. During PBD treatment the ratio area under the thalamic ECF concentration-time curve/area under the ventricular CSF concentration-time curve approached unity. These results provide evidence that AZT is actively transported outwardly across the CSF- and brain ECF-blood barriers, and this transport system is sensitive to PBD. A pharmacokinetic model that considers the effect of PBD on the AZT clearance from brain to plasma suggests that 73% of this pathway is subject to competitive inhibition by PBD.
Wong
S L
SL
Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis.
Van Belle
K
K
Sawchuk
R J
RJ
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001921:Brain / Q000378:metabolism*; D003956:Dialysis; D005110:Extracellular Space / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D011339:Probenecid / Q000494:pharmacology*; D011817:Rabbits; D015215:Zidovudine / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*
D015215:Zidovudine; D011339:Probenecid