Abstract
The distribution of zidovudine (3′-azido-3′-deoxythymidine; AZT) into two regions of rabbit brain was investigated in crossover using microdialysis. Six rabbits had guide cannulas surgically implanted in the lateral ventricle and thalamus by stereotaxic placement. After recovery, microdialysis probes were positioned and i.v. bolus doses of 5, 10, 20, and 30 mg/kg were administered to each animal over a period of 2 weeks. Blood was drawn via a marginal ear vein catheter for 8 hr. Brain dialysate was collected at 3 µl/min from ventricle and thalamus dialysis probes every 10 min. Simulated cerebrospinal fluid (CSF), to which 3′-azido-2′,3′-dideoxyuridine (AZdU) was added, was used as perfusate. AZdU loss, which was measured during simultaneous retrodialysis, served as a marker for in vivo recovery of AZT. AZT concentrations in plasma, as well as in ventricle and thalamus dialysate, were determined using a sensitive HPLC assay, and AZdU was simultaneously analyzed in the dialysates. Calculation of in vivo recovery of AZT was based on loss of AZdU from the perfusate during retrodialysis and was used to estimate the concentration of drug at both sites in the brain. In vitro loss of AZdU and recovery of AZT showed good agreement, demonstrating a bivariate regression slope of 0.99. The half-lives and AUCs (normalized to dose) achieved in the plasma, ventricle, or thalamus were not significantly different for the four doses. The AUC ratios, which represent the ratio of clearances into and from the CNS, were not significantly different among the doses studied (AUCv/AUCp range, 0.16–0.19; AUCt/AUCp range, 0.05–0.09), providing further evidence that the kinetics of distribution into the thalamus and CSF are linear. The results also demonstrate that the time-averaged concentrations of AZT in thalamus ECF are about half of those in the CSF.
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REFERENCES
D. M. Barnes. Promising results halt trial of anti-AIDS drug. Science 234:15–16 (1986).
P. S. Gill, M. Rarick, R. K. Brynes, D. Causey, C. Loureiro, and A. M. Levine. Azidothymidine associated with bone marrow failure in the acquired immunodeficiency syndrome (AIDS). Ann. Intern. Med. 107:502–505 (1987).
S. L. Nightingale. Lower dosage for zidovudine: Revised labeling. JAMA 263:1476 (1990).
L. G. Epstein and L. R. Sharer. Neurology of human immunodeficiency virus infection in children. In M. L. Rosenblum, R. M. Levy, and D. E. Bredesen (eds.), AIDS and the Nervous System, Raven Press, New York, 1988, pp. 79–101.
R. W. Price, B. Brew, J. Sidtis, M. Rosenblum, A. C. Scheck, and P. Cleary. The brain in AIDS: Central nervous system HIV-1 infection and AIDS dementia complex. Science 239:586–592 (1988).
H. Budka. Multinucleated giant cells in brain: A hall mark of the acquired immune deficiency syndrome (AIDS). Acta Neuropathol. 69:253–258 (1986).
L. R. Sharer, E.-S. Cho, and L. G. Epstein. Multinucleated giant cells and HTLV-III in AIDS encephalopathy. Hum. Pathol. 16:760 (1985).
J. Michaels, L. R. Sharer, and L. G. Epstein. Human immunodeficiency virus type 1 (HIV-1) infection of the nervous system: a review. Immunodef. Rev. 1:71–104 (1988).
B. A. Navia, E. S. Cho, C. K. Petito, and R. W. Price. The AIDS dementia complex. II. Neuropathology. Ann. Neurol. 19:525–535 (1986).
R. A. Hawkins, M. E. Phelps, S.-C. Huang, J. A. Wapenski, P. D. Grimm, R. G. Parker, G. Juillard, and P. Greenberg. A kinetic evaluation of blood-brain barrier permeability in human brain tumors with 68Ga-EDTA and positron computed tomography. J. Cereb. Blood Flow Metab. 4:507–515 (1984).
D. J. Brooks, R. P. Beaney, A. A. Lammertsma, S. Herold, D. R. Turton, S. K. Luthra, R. S. J. Frackowiak, D. G. T. Thomas, J. Marshall, and T. Jones. Glucose transport across the blood-brain barrier in normal human subjects and patients with cerebral tumours studies using [11C]-3-O-methyl-D-glucose and positron emission tomography. J. Cereb. Blood Flow Metab. 6:230–239 (1986).
U. Ungerstedt and A. Hallstrom. In vivo microdialysis—a new approach to the analysis of neurotransmitters in the brain. Life Sci. 41:861–864 (1987).
H. Benveniste. Short review: Brain dialysis. J. Neurochem. 52:1667–1679 (1989).
K. M. Kendrick. Use of microdialysis in neuroendocrinology. Methods Enzymol. 168:182–197 (1989).
K. E. Sabol and C. R. Freed. Brain acetaminophen measurement by in vivo dialysis, in vivo electrochemistry and tissue assay: A study of the dialysis technique in the rat. J. Neurosci. Meth. 24:163–168 (1988).
D. O. Scott, L. R. Sorenson, K. L. Steele, D. L. Puckett, and C. E. Lunte. In vivo microdialysis sampling for pharmacokinetic investigations. Pharm. Res. 8(3):389–392 (1991).
Y. Wang, S. L. Wong, and R. J. Sawchuk. Comparison of in vitro and in vivo calibration of microdialysis probes using retrodialysis. Curr. Separ. 10:87 (1991).
Y. Wang, S. L. Wong, and R. J. Sawchuk. In vitro and in vivo microdialysis calibration using retrodialysis: Application to a study of the distribution of zidovudine to rabbit CSF and thalamus (submitted for publication).
C. H. Sawyer, J. W. Everett, and G. Galand. The rabbit diencephalon in stereotaxic coordinates. J. Comp. Neurol. 101:801–824 (1954).
C. Kozma, W. Macklin, L. M. Cummins, and R. Mauer. The anatomy, physiology, and the biochemistry of the rabbit. In S. H. Weisbroth, R. E. Flatt, and A. L. Kraus (eds.), The Biology of the Laboratory Rabbit, Academic Press, New York, 1974, pp. 49–72.
M. A. Hedaya and R. J. Sawchuk. A sensitive liquid-chromatography method for determination of 3′-azido-3′-deoxythymidine (AZT) in plasma and urine. Clin. Chem. 34:1565–1568 (1988).
M. Gibaldi and D. Perrier. Pharmacokinetics, 2nd ed., Marcel Dekker, New York, 1982.
M. A. Hedaya and R. J. Sawchuk. Effect of probenecid on the renal and nonrenal clearances of zidovudine and its distribution into cerebrospinal fluid in the rabbit. J. Pharm. Sci. 78:716–722 (1989).
R. J. Sawchuk and M. A. Hedaya. Modeling the enhanced uptake of zidovudine (AZT) into cerebrospinal fluid. 1. Effect of probenecid. Pharm. Res. 7(4):332–338 (1990).
S. L. Wong, M. A. Hedaya, and R. J. Sawchuk. Competitive inhibition of zidovudine clearance by probenecid during continuous coadministration (submitted for publication).
J. M. Collins, R. W. Klecker Jr., J. A. Kelley, J. S. Roth, C. L. McCully, F. M. Balis, and D. G. Poplack. Pyrimidine dideoxyribonucleosides: Selectively of penetration into cerebrospinal fluid. J. Pharmacol. Exp. Ther. 245(2):466–470 (1988).
T. P. Zimmerman, W. B. Mahony, and K. L. Prus. 3′-Azido-3′deoxythymidine: An unusual nucleoside analogue that permeates the membrane of human erthrocytes and lymophytes by nonfacilitated diffusion. J. Biol. Chem. 262(12):5748–5754 (1987).
M. A. Hedaya, W. F. Elmquist, and R. J. Sawchuk. Probenecid inhibits the metabolic and renal clearances of zidovudine (AZT) in human volunteers. Pharm. Res. 7:411–417 (1990).
R. W. Klecker, J. M. Collins, R. Yarchoan, R. Thomas, J. F. Jenkins, S. Broder, and C. E. Myers. Plasma and cerebrospinal fluid pharmacokinetics of 3′-azido-3′-deoxythymidine: A novel pyrimidine analog with potential application for the treatment of patients with AIDS and related diseases. Clin. Pharmacol. Ther. 41:407–412 (1987).
P. A. Pizzo, J. Eddy, J. Falloon, F. Balis, R. F. Murphy, H. Moss, P. Wolters, P. Brouwers, P. Jarosinski, M. Rubin, S. Broder, R. Yarchoan, A. Brunetti, M. Maha, S. Lehrman, and D. G. Poplack. Effect of continuous intravenous infusion of zidovudine (AZT) in children with symptomatic HIV infection. N. Engl. J. Med. 319:889–896 (1988).
T. Terasaki and W. M. Pardridge. Restricted transport of 3′-azido-3′-deoxythymidine and dideoxynucleosides through the blood-brain barrier. J. Infect. Dis. 158(3):630–632 (1988).
E. M. Cornford and W. H. Oldendorf. Independent blood-brain barrier transport systems for nucleic acid precursors. Biochim. Biophys. Acta 394:211–219 (1975).
R. A. Hawkins, A. L. Miller, J. E. Cremer, and R. L. Veech. J. Neurochem. 23:917–923 (1974).
K. Henry, B. J. Chinnock, R. P. Quinn, C. V. Fletcher, P. de Miranda, and H. H. Balfour, Jr. Concurrent zidovudine levels in semen and serum determined by radioimmunoassay in patients with AIDS or AIDS-related complex. JAMA 259:3023–3026 (1988).
J. M. Gallo, L. N. Clark, and J. T. Rubino. Pump delivery of azidothymidine: Potential for constant concentrations and improved brain delivery. J. Control. Release 9:249–253 (1989).
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Wong, S.L., Wang, Y. & Sawchuk, R.J. Analysis of Zidovudine Distribution to Specific Regions in Rabbit Brain Using Microdialysis. Pharm Res 9, 332–338 (1992). https://doi.org/10.1023/A:1015834701136
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DOI: https://doi.org/10.1023/A:1015834701136