Abstract
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 (Vbr) 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 Vbr, 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 (PSBBB,eff) across the blood-brain barrier (BBB) and the symmetrical permeability clearance (PSBBB) across the BBB for AZT were calculated as 179 and 10.3 μl/min/g brain, respectively. The efflux transport clearance (PSCSF,eff) across the blood-cerebrospinal fluid barrier (BCSFB) and the symmetrical permeability clearance (PSCSF) across the BCSFB for AZT were calculated as 227 and 28.3 μl/min/ml CSF, respectively. For the distribution of DDI, the PSBBB,eff and PSBBBwere 79.2 and 2.03 μl/min/g brain, respectively, while the PSCSF,eff and PSCSF 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.
Footnotes
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Send reprint requests to: Yuichi Sugiyama. Ph.D., Professor, Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, The University of Tokyo, Hongo 7–3-1, Bunkyo-ku, Tokyo 113, Japan.
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↵1 This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture, Japan and by grants from the Japan Health Sciences Foundation Drug Innovation Project.
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↵2 Current address: Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Tohoku University, Aoba, Aramakiaza, Aoba-ku, Sendai 980–77, Japan.
- Abbreviations:
- AZT
- 3′-azido-3′-deoxythymidine
- DDI
- 2′,3′-dideoxyinosine
- PAH
- p-aminohippuric acid
- DIDS
- 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid
- BBB
- blood-brain barrier
- BCSFB
- blood-cerebrospinal fluid barrier
- BEI
- brain efflux index
- CNS
- central nervous system
- CSF
- cerebrospinal fluid
- ISF
- interstitial fluid
- AIDS
- acquired immunodeficiency syndrome
- ADC
- AIDS-dementia complex
- HIV
- human immunodeficiency virus
- Dw, diffusion coefficient in water
- Dt,diffusion coefficient in brain tissue
- HPLC
- high-performance liquid chromatography
- i.c.v.
- intracerebroventricular
- S/M ratio
- slice-to-medium concentration ratio
- AUC
- area under the concentration-time curve
- Received September 10, 1996.
- Accepted May 16, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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