Brain cyclosporin A levels are determined by ontogenic regulation of mdr1a expression.
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.
Goralski
Kerry B
KB
Department of Pharmacology, Dalhousie University, Room 5E Sir Charles Tupper Building, 5850 College Street, Halifax, Nova Scotia, Canada B3H 1X5.
Acott
Philip D
PD
Fraser
Albert D
AD
Worth
David
D
Sinal
Christopher J
CJ
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism*; D016572:Cyclosporine / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D005786:Gene Expression Regulation; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics*; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D012737:Sex Factors; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D016572:Cyclosporine; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C095122:multidrug resistance protein 3