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

• Published in: Drug metabolism and disposition Vol. 34; no. 2; pp. 288 - 295
• Main Authors: GORALSKI, Kerry B, ACOTT, Philip D, FRASER, Albert D, WORTH, David, SINAL, Christopher J
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01.02.2006
• Subjects: Age Factors; Animals; Animals, Newborn; ATP Binding Cassette Transporter, Subfamily B - deficiency; ATP Binding Cassette Transporter, Subfamily B - genetics; ATP Binding Cassette Transporter, Subfamily B - metabolism; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; ATP-Binding Cassette Sub-Family B Member 4; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Biological and medical sciences; Brain - metabolism; Cyclosporine - blood; Cyclosporine - pharmacokinetics; Female; Gene Expression Regulation; Immunosuppressive Agents - blood; Immunosuppressive Agents - pharmacokinetics; Kidney - metabolism; Liver - metabolism; Male; Medical sciences; Mice; Mice, Knockout; Pharmacology. Drug treatments; RNA, Messenger - metabolism; Sex Factors; Ciclosporin; Immunosuppressive agent; Central nervous system; Encephalon
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.105.007427

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 3 H-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.