Vol. 282, Issue 3, 1509-1517, 1997

Distributed Model Analysis of 3-Azido-3-Deoxythymidine and 2,3-Dideoxyinosine Distribution in Brain Tissue and Cerebrospinal Fluid¹

Katsuko Takasawa, Tetsuya Terasaki² , Hiroshi Suzuki, Tsuyoshi Ooie and Yuichi Sugiyama

Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113, Japan (K.T., T.T., H.S. and Y.S.), Central Research Laboratories, Kyorin Pharmaceutical Co., Ltd., Nogi 2399-1, Nogi-machi, Shimotsuga-gun, Tochigi 329-01, Japan (T.O.)

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 µl/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 µl/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 µl/min/ml CSF, respectively. For the distribution of DDI, the PS_BBB,eff and PS_BBB were 79.2 and 2.03 µl/min/g brain, respectively, while the PS_CSF,eff and PS_CSF for DDI were 196 and 5.88 µl/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.