Goralski Kerry B, Acott Philip D, Fraser Albert D, Worth David, Sinal Christopher J
Department of Pharmacology, Dalhousie University, Room 5E Sir Charles Tupper Building, 5850 College Street, Halifax, Nova Scotia, Canada B3H 1X5.
Drug Metab Dispos. 2006 Feb;34(2):288-95. doi: 10.1124/dmd.105.007427. Epub 2005 Nov 22.
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.
环孢素A（CyA）毒性在小儿器官移植患者中很常见。我们推测新生和发育中的小鼠体内mdr1a表达降低会影响CyA在器官内的蓄积和/或毒性。为进行功能研究，对1日龄、12日龄、19日龄的成年雄性和雌性mdr1a+/+和mdr1a-/-小鼠腹腔注射CyA（5 mg kg(-1)）。1日龄、12日龄和19日龄小鼠的血药峰浓度（1000 ng ml(-1)）低于成年小鼠（1500 ng ml(-1)），但mdr1a+/+和mdr1a-/-小鼠相似。通过定量聚合酶链反应测量，19日龄雄性和雌性小鼠肾脏mdr1a表达增加2.5倍，成年雌性小鼠比成年雄性小鼠又增加4倍。与新生小鼠相比，肝脏mdr1a表达在12日龄时增加6倍。此后，观察到雌性肝脏mdr1a表达维持不变，而雄性降至新生水平。肾脏/血液（8至9倍）和肝脏/血液（12至15倍）的CyA水平在12日龄和19日龄时最高，且不依赖于mdr1a mRNA水平的成熟变化。与1日龄小鼠相比成人mdr1a mRNA脑表达更高（3倍），免疫可检测的P-糖蛋白相应增加5倍，脑内CyA蓄积降低80%。相反，在mdr1a基因敲除小鼠中，新生和成年小鼠脑/血CyA相似。对于mdr1a底物3H-地高辛的脑内蓄积也观察到类似模式。我们得出结论，由于P-糖蛋白发育不全，新生儿或幼儿发生中枢神经系统药物毒性的风险可能更高。
