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Drug Metabolism and Disposition Fast Forward
First published on November 22, 2005; DOI: 10.1124/dmd.105.007427

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Received for publication September 19, 2005.
Revised November 8, 2005.
Accepted for publication November 9, 2005.

Brain Cyclosporine A Levels Are Determined By Ontogenic Regulation Of Mdr1a Expression

Kerry B Goralski 1, Philip D Acott 2, Albert D Fraser 1, David Worth 3, Christopher J Sinal 1*

1 Dalhousie University 2 IWK Health Centre and Dalhousie University 3 Queen Elizibeth II Health Science Centre

* Address correspondence to: E-mail: csinal{at}dal.ca

Abstract

Cyclosporine A (CyA) toxicity is a common occurrence in pediatric organ transplant patients. We hypothesized that reduced mdr1a expression in newborn and developing mice would affect CyA accumulation within organs and/or toxicity. For functional studies, CyA was administered (5 mg kg-1 i.p.) to 1, 12, 19 day and adult male and female mdr1a+/+ and mdr1a-/- mice. Peak blood CyA was lower in 1, 12 and 19- day-old (1000 ng ml-1) versus adult (1500 ng ml-1) mice but was similar in mdr1a+/+ and mdr1a-/- mice. Kidney mdr1a expression (measured by quantitative PCR) increased 2.5- fold in 19-day-old male and female mice and increased a further 4-fold in adult females compared to adult males. Liver mdr1a expression increased 6-fold by day 12 compared to neonatal mice. Thereafter, maintenance of hepatic mdr1a expression in females and a reduction to neonatal levels in males was observed. Kidney/blood (8-9 fold) and liver/blood (12-15 fold) CyA were highest on day 12 and 19 and not dependent on maturational changes in mdr1a mRNA levels. Adults had higher brain expression of mdr1a mRNA (3-fold), a corresponding 5-fold increase in immunodetectable P-glycoprotein and 80% lower brain accumulation of CyA compared to 1- day-old mice. Conversely, in mdr1a-null mice, brain/blood CyA was similar in newborn and adults. A similar pattern was observed for the brain accumulation of the mdr1a substrate 3H-digoxin. We conclude that the risk for CNS drug toxicity could be higher in neonates or young children as a consequence of under-developed P- glycoprotein.


Key words: ABC transporters, blood-CNS transport, drug distribution, drug toxicity, drug transport, gender differences, immunosuppression, p-glycoprotein, renal disposition


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