Effect of Age on Distribution of Zidovudine (Azidothymidine) into the Cerebrospinal Fluid of Macaca nemestrina

Abstract

The brain tissue is an important target for anti-HIV drug therapy. Since the permeability of the blood–brain and blood–cerebrospinal fluid (CSF) barriers may differ between neonates and adults, we have determined the effect of age on the distribution of zidovudine (ZDV or azidothymidine) into the CSF in the macaque (M. nemestrina). Five newborn macaques were administered ZDV (iv bolus, 5 mg/kg) at various ages (2 days to 4 months). Both CSF (cisternal) and venous blood samples were obtained at approximately 60 and 90 min after drug administration. In another series of experiments, adult female macaques received ZDV as either an iv bolus (5 and 10 mg/kg) or an infusion for at least 12 hr. CSF (lumbar) and venous blood samples were obtained at approximately 60 and 90 min after iv bolus and at more than 12 hr after iv infusion. ZDV concentration in the CSF and the plasma samples was determined by high-performance liquid chromatography. The CSF/plasma concentration ratio of ZDV in the newborn and adult macaques, after iv bolus administration, was independent of time. In addition, no significant (P > 0.05) difference was observed in the pooled iv bolus ZDV CSF/plasma concentration ratio between the adult group (0.236 ± 0.058) and the newborns (0.213 ± 0.039). Moreover, the ZDV CSF/plasma concentration ratio in the adults and the newborns, after iv bolus administration, was found not to be significantly (P > 0.05) different from the ratio obtained at steady state in the adults (0.224 ± 0.094). These data indicate that the distribution of ZDV into the CSF in macaque neonates and adults is similar.

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REFERENCES

  1. 1.

    R. M. Levy and D. E. Bredesen. Central nervous system dysfunction in acquired immunodeficiency syndrome. In M. L. Rosenblum et al. (eds.), AIDS and the Nervous System, Raven Press, New York, 1988, pp. 29–63.

    Google Scholar 

  2. 2.

    A. L. Belman, G. Diamond, D. Dickson, D. Horoupian, J. Llena, G. Lantos, and A. Rubinstein. Pediatric acquired immunodeficiency syndrome: Neurological syndromes. Am. J. Dis. Child. 142:29–35 (1988).

    Google Scholar 

  3. 3.

    P. A. Pizzo, J. Eddy, J. Falloon, et al. Effect of continuous intravenous infusion of zidovudine (AZT) in children with symptomatic HIV infection. N. Engl. J. Med. 319:889–896 (1988).

    Google Scholar 

  4. 4.

    K. M. Butler, R. N. Husson, F. M. Balis, et al. Dideoxyinosine in children with symptomatic human immunodeficiency virus infection. N. Engl. J. Med. 324:137–144 (1991).

    Google Scholar 

  5. 5.

    R. Yarchoan, J. M. Pluda, R. V. Thomas, et al. Long-term toxicity/activity profile of 2′,3′-dideoxyinosine in AIDS or AIDS-related complex. Lancet 336:526–529 (1990).

    Google Scholar 

  6. 6.

    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).

    Google Scholar 

  7. 7.

    F. M. Balis, P. A. Pizzo, R. F. Murphy, et al. The pharmacokinetics of zidovudine administered by continuous infusion in children. Ann. Intern. Med. 110:279–285 (1989).

    Google Scholar 

  8. 8.

    C. E. Johanson. Ontogeny and phylogeny of the blood-brain barrier. In E. A. Neuwelt (ed.), Implications of the Blood-Brain Barrier and Its Manipulation, Plenum Medical Book, New York, 1989, p. 179.

    Google Scholar 

  9. 9.

    A. Lopez-Anaya, J. D. Unadkat, L. A. Schumann, and A. L. Smith. Pharmacokinetics of zidovudine (azidothymidine). II. Development of metabolic and renal clearance pathways in the neonate. J. Acquir. Immune Defic. Syndr. 3:1052–1058 (1990).

    Google Scholar 

  10. 10.

    A. Lopez-Anaya, J. D. Unadkat, L. A. Schumann, and A. L. Smith. Pharmacokinetics of zidovudine (azidothymidine). III. Effect of pregnancy. J. Acquir. Immune Defic. Syndr. 4:64–68 (1991).

    Google Scholar 

  11. 11.

    A. Lopez-Anaya, J. D. Unadkat, L. A. Schumann, and A. L. Smith. Pharmacokinetics of zidovudine (azidothymidine). I. Transplacental transfer. J. Acquir. Immune Defic. Syndr. 3:959–964 (1990).

    Google Scholar 

  12. 12.

    J. M. Collins and J. D. Unadkat. Clinical pharmacokinetics of zidovudine. Clin. Pharmacokinet. 17:1–9 (1989).

    Google Scholar 

  13. 13.

    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).

    Google Scholar 

  14. 14.

    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).

    Google Scholar 

  15. 15.

    M. A. Peters. Development of a “blood-brain barrier” to methadone in the newborn rat. J. Pharmacol. Exp. Ther. 192:513–520 (1975).

    Google Scholar 

  16. 16.

    A. M. Jakobson. Bilirubin accumulation by the rabbit choroid plexus in vitro. Biol. Neonate 60:221–229 (1991).

    Google Scholar 

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Correspondence to Jashvant D. Unadkat.

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Lopez-Anaya, A., Unadkat, J.D., Calkins, D.F. et al. Effect of Age on Distribution of Zidovudine (Azidothymidine) into the Cerebrospinal Fluid of Macaca nemestrina . Pharm Res 10, 1338–1340 (1993). https://doi.org/10.1023/A:1018977915364

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  • CSF
  • plasma
  • zidovudine
  • azidothymidine
  • infant
  • neonate
  • macaques
  • AIDS
  • CSF–blood barrier
  • biological transport