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BRAIN CYCLOSPORIN A LEVELS ARE DETERMINED BY ONTOGENIC REGULATION OF MDR1A EXPRESSION

Department of Pharmacology (K.B.G., P.D.A., C.J.S.), Department of Pediatrics (K.B.G., P.D.A.), and Department of Pathology (A.D.F.), Dalhousie University, Halifax, Nova Scotia, Canada; IWK Health Centre, Halifax, Nova Scotia, Canada (K.B.G., P.D.A.); and Toxicology Laboratory, Capital Health, Queen Elizabeth II Sciences Centre, Halifax, Nova Scotia, Canada (A.D.F., D.W.)

Cyclosporin 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-, and 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 polymerase chain reaction) increased 2.5-fold in 19-day-old male and female mice and increased another 4-fold in adult females compared with adult males. Liver mdr1a expression increased 6-fold by day 12 compared with neonatal mice. Thereafter, maintenance of hepatic mdr1a expression in females and a reduction to neonatal levels in males was observed. Kidney/blood (8- to 9-fold) and liver/blood (12- to 15-fold) CyA levels were highest on days 12 and 19 and were 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 with 1-day-old mice. Conversely, in mdr1a-null mice, brain/blood CyA was similar in newborn and adult mice. A similar pattern was observed for the brain accumulation of the mdr1a substrate ³H-digoxin. We conclude that the risk for central nervous system drug toxicity could be higher in neonates or young children as a consequence of underdeveloped P-glycoprotein.

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