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Research ArticleArticle

CONTRARY TO ADULT, NEONATAL RATS SHOW PRONOUNCED BRAIN UPTAKE OF CORTICOSTEROIDS

Vikram Arya, Vincent G. Demarco, Manish Issar and Günther Hochhaus
Drug Metabolism and Disposition June 2006, 34 (6) 939-942; DOI: https://doi.org/10.1124/dmd.105.007419
Vikram Arya
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Vincent G. Demarco
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Manish Issar
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Günther Hochhaus
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Abstract

Neurotoxic adverse effects after systemic corticosteroid administration are elevated in preterm infants. To test whether this might be related to an immature blood-brain barrier (BBB) that permits corticosteroids to enter the brain and induce neurotoxic effects, this study assessed the differences in brain permeability of triamcinolone acetonide after intratracheal administration to neonatal (10- to 11-day-old) and adult rats. Triamcinolone acetonide (or the phosphate prodrug in the case of neonatal rats) was administered intratracheally to neonatal rats at doses of 2.5, 25, or 50 μg/kg and to adult rats at 100 μg/kg. An ex vivo receptor binding assay was used to monitor the cumulative brain and liver glucocorticoid receptor occupancies over 6 h. Brain and liver receptor occupancies in neonates were similar for the 25 and 50 μg/kg triamcinolone acetonide phosphate (brain/liver receptor occupancy ratio, 1.10 ± 0.14 and 0.87 ± 0.13, respectively), whereas some reduction in the brain permeability was seen at the lower dose. After intratracheal administration of 100 μg/kg triamcinolone acetonide to adult rats, receptor occupancies in the brain were significantly lower (brain/liver ratio, 0.21 ± 0.14; p < 0.001). The study demonstrated that glucocorticoids enter the brain of neonatal rats because of an immature BBB. The results of this study support the hypothesis that neurotoxic adverse effects in preterm infants after systemic corticosteroid administration might be related to an immature BBB.

Footnotes

  • This study was supported by the Research Opportunity Fund of the University of Florida Research Foundation.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.105.007419.

  • ABBREVIATIONS: CLD, chronic lung disease(s); P-gp, P-glycoprotein; BBB, blood-brain barrier; TAP, triamcinolone acetonide phosphate; TA, triamcinolone acetonide; AUC0-6h, area under the free receptor-time profile calculated over a 6-h time period.

  • ↵1 Current affiliation: Sandoz, Wilson, NC.

    • Received September 16, 2005.
    • Accepted February 22, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 34 (6)
Drug Metabolism and Disposition
Vol. 34, Issue 6
1 Jun 2006
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Research ArticleArticle

CONTRARY TO ADULT, NEONATAL RATS SHOW PRONOUNCED BRAIN UPTAKE OF CORTICOSTEROIDS

Vikram Arya, Vincent G. Demarco, Manish Issar and Günther Hochhaus
Drug Metabolism and Disposition June 1, 2006, 34 (6) 939-942; DOI: https://doi.org/10.1124/dmd.105.007419

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Research ArticleArticle

CONTRARY TO ADULT, NEONATAL RATS SHOW PRONOUNCED BRAIN UPTAKE OF CORTICOSTEROIDS

Vikram Arya, Vincent G. Demarco, Manish Issar and Günther Hochhaus
Drug Metabolism and Disposition June 1, 2006, 34 (6) 939-942; DOI: https://doi.org/10.1124/dmd.105.007419
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