Distributed model analysis of 3'-azido-3'-deoxythymidine and 2',3'-dideoxyinosine distribution in brain tissue and cerebrospinal fluid.
The restricted distribution of 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxyinosine (DDI) in brain tissue and cerebrospinal fluid (CSF) has been analyzed using the distributed model. The distribution volume of AZT and DDI in brain tissue (V(br)) was found to be 1.07 +/- 0.09 and 0.727 +/- 0.030 ml/g brain, respectively, in an in vitro brain slice uptake study. The pharmacokinetic parameters were obtained by fitting the concentration-time profiles of AZT and DDI in brain tissue and CSF after i.v. or i.c.v. administration taking the value of V(br), the CSF bulk flow rate (2.9 microl/min), and the surface area of the cerebroventricular ependyma (2.0 cm2), using a nonlinear least squares program combined with a fast inverse Laplace transform. The efflux transport clearance (PS(BBB,eff)) across the blood-brain barrier (BBB) and the symmetrical permeability clearance (PS(BBB)) across the BBB for AZT were calculated as 179 and 10.3 microl/min/g brain, respectively. The efflux transport clearance (PS(CSF,eff)) across the blood-cerebrospinal fluid barrier (BCSFB) and the symmetrical permeability clearance (PS(CSF)) across the BCSFB for AZT were calculated as 227 and 28.3 microl/min/ml CSF, respectively. For the distribution of DDI, the PS(BBB,eff) and PS(BBB) were 79.2 and 2.03 microl/min/g brain, respectively, while the PS(CSF,eff) and PS(CSF) for DDI were 196 and 5.88 microl/min/ml CSF, respectively. Based on simulation studies using the fitted parameters, a significant degree of efflux transport across the BBB and BCSFB has been suggested to be responsible for the restricted distribution of AZT and DDI in brain tissue and CSF, respectively.
Takasawa
K
K
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, The University of Tokyo, Japan.
Terasaki
T
T
Suzuki
H
H
Ooie
T
T
Sugiyama
Y
Y
D000818:Animals; D019380:Anti-HIV Agents / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D016049:Didanosine / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D008297:Male; D008954:Models, Biological; D051381:Rats; D017208:Rats, Wistar; D015215:Zidovudine / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*
D019380:Anti-HIV Agents; D015215:Zidovudine; D016049:Didanosine