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'-deoxthymidine (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 a nd 0.727 +/- 0.030 ml/g brain, respectively, in an in vitro brain slic e uptake study. The pharmacokinetic parameters were obtained by fittin g the concentration-time profiles of AZT and DDI in brain tissue and C SF after i.v. or i.c.v. administration taking the value of V-br, the C SF bulk flow rate (2.9 mu l/min), and the surface area of the cerebrov entricular ependyma (2.0 cm(2)), using a nonlinear least squares progr am combined with a fast inverse Laplace transform. The efflux transpor t clearance (PSBBB,eff) across the blood-brain barrier (BBB) and the s ymmetrical permeability clearance (PSBBB) across the BBB for AZT were calculated as 179 and 10.3 mu l/min/g brain, respectively. The efflux transport clearance (PSCSF,eff) across the blood-cerebrospinal fluid b arrier (BCSFB) and the symmetrical permeability clearance (PSCSF) acro ss the BCSFB for AZT were calculated as 227 and 28.3 mu l/min/ml CSF, respectively. For the distribution of DDI, the PSBBB,eff and PSBBB wer e 79.2 and 2.03 mu l/min/g brain, respectively, while the PSCSF,eff an d PSCSF for DDI were 196 and 5.88 mu l/min/ml CSF, respectively. Based on simulation studies using the fitted parameters, a significant degr ee 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.