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Brain cyclosporin A levels are determined by ontogenic regulation of mdr1a expression

Kerry B Goralski1, Philip D Acott, Albert D Fraser

  • 1Department of Pharmacology, Dalhousie University, Room 5E Sir Charles Tupper Building, 5850 College Street, Halifax, Nova Scotia, Canada B3H 1X5.

Drug Metabolism and Disposition: the Biological Fate of Chemicals
|November 24, 2005
PubMed

Insights

Neonatal mice show higher Cyclosporin A (CyA) brain accumulation due to underdeveloped P-glycoprotein. This suggests increased central nervous system drug toxicity risk in young children, impacting pediatric organ transplant outcomes.

Area of Science:

  • Pharmacology
  • Developmental Biology
  • Toxicology

Background:

  • Cyclosporin A (CyA) toxicity is a significant concern in pediatric organ transplant recipients.
  • The P-glycoprotein transporter, encoded by the mdr1a gene, plays a crucial role in drug efflux and barrier protection.
  • Maturational changes in mdr1a expression may influence CyA pharmacokinetics and toxicity in developing individuals.

Purpose of the Study:

  • To investigate the impact of developmental changes in mdr1a expression on Cyclosporin A (CyA) accumulation and toxicity in mice.
  • To determine if reduced mdr1a expression in neonates contributes to increased central nervous system (CNS) drug exposure.
  • To assess the relationship between P-glycoprotein maturation and CyA brain penetration in early life.

Main Methods:

  • Administration of Cyclosporin A (CyA) to mice of different ages (1-day, 12-day, 19-day, and adult) and genotypes (mdr1a+/+ and mdr1a-/-).
  • Quantification of CyA blood, kidney, liver, and brain levels using validated assays.
  • Measurement of mdr1a mRNA expression in various organs via quantitative polymerase chain reaction (qPCR).
  • Assessment of P-glycoprotein levels through immunodetection.
  • Evaluation of brain accumulation of a known mdr1a substrate (3H-digoxin).

Main Results:

  • Peak blood CyA levels were lower in young mice compared to adults but similar between mdr1a+/+ and mdr1a-/- mice.
  • Kidney and liver mdr1a expression increased significantly with age, with distinct patterns in males and females.
  • Brain mdr1a mRNA and P-glycoprotein levels were significantly lower in 1-day-old mice compared to adults.
  • Brain CyA accumulation was substantially higher in 1-day-old mice, an effect absent in mdr1a-null mice.
  • Similar age-dependent patterns were observed for brain accumulation of 3H-digoxin.

Conclusions:

  • Underdeveloped P-glycoprotein function in neonatal and young mice leads to increased brain accumulation of Cyclosporin A.
  • The findings suggest a higher risk of central nervous system drug toxicity in neonates and young children due to immature P-glycoprotein.
  • These results highlight the importance of considering developmental changes in drug transporter expression for optimizing pediatric drug therapy and minimizing toxicity.

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